Ca2+ insensitive EF hand; EF hands are helix-loop-helix binding motifs involved in the regulation of many cellular processes. EF hands usually bind to Ca2+ ions which causes a major conformational change that allows the protein to interact with its designated targets. This domain corresponds to an EF hand which has partially or entirely lost its calcium-binding properties. The calcium insensitive EF hand is still able to mediate protein-protein recognition.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1720370339 601 DTDTADQVMASFKILAGDKNYITEDELRRELPPDQAEYCIARMAPYAGP--DSVPGALDYMSFSTALYG 667
Cdd:pfam08726   1 DTDTAEQVEASFRALAGGKPYVTEEDLRRELTPDQAEYCIARMPPYSGPdgDSVPGAYDYVSFSEALFG 69

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339  34 EDYEKLASDLLEWIRRTIPWLENRVPENTMHAMQQKLEDFRDYRR--LHKPPKVQEkcqleinFNTLQTKLRLSNRPAfM 111
Cdd:cd00176     3 QQFLRDADELEAWLSEKEELLSSTDYGDDLESVEALLKKHEALEAelAAHEERVEA-------LNELGEQLIEEGHPD-A 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 112 PSEGRMVSDINNAWGCLEQAEKGYEEWLLNEIRRLERLDHLAEKfrqkasihEAWTDGKEAMLRQKDYETaTLSEIKALL 191
Cdd:cd00176    75 EEIQERLEELNQRWEELRELAEERRQRLEEALDLQQFFRDADDL--------EQWLEEKEAALASEDLGK-DLESVEELL 145

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1720370339 192 KKHEAFESDLAAHQDRVEQIAAIAQEL-NELDYYDSPSVNARCQKICDQWDNLGALTQKRREALE 255
Cdd:cd00176   146 KKHKELEEELEAHEPRLKSLNELAEELlEEGHPDADEEIEEKLEELNERWEELLELAEERQKKLE 210

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 391 QFGAQANVIGPWIQTKMEEIgriSIEMHG----TLEDQLSHLRQYEKSIVNYKPKIDQLECDHQLIQEALIFDNKHTNYN 466
Cdd:pfam00435   5 QFFRDADDLESWIEEKEALL---SSEDYGkdleSVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQER 81

                          90       100
                  ....*....|....*....|....
gi 1720370339 467 MEHIRVGWEQLLTTIARTINEVEN 490
Cdd:pfam00435  82 LEELNERWEQLLELAAERKQKLEE 105

Ca2+ insensitive EF hand; EF hands are helix-loop-helix binding motifs involved in the regulation of many cellular processes. EF hands usually bind to Ca2+ ions which causes a major conformational change that allows the protein to interact with its designated targets. This domain corresponds to an EF hand which has partially or entirely lost its calcium-binding properties. The calcium insensitive EF hand is still able to mediate protein-protein recognition.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1720370339 601 DTDTADQVMASFKILAGDKNYITEDELRRELPPDQAEYCIARMAPYAGP--DSVPGALDYMSFSTALYG 667
Cdd:pfam08726   1 DTDTAEQVEASFRALAGGKPYVTEEDLRRELTPDQAEYCIARMPPYSGPdgDSVPGAYDYVSFSEALFG 69

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 151 HLAEKFRQKASIHEAWTDGKEAMLRQKDYETaTLSEIKALLKKHEAFESDLAAHQDRVEQIAAIAQELNELDYYDSPSVN 230
Cdd:pfam00435   1 LLLQQFFRDADDLESWIEEKEALLSSEDYGK-DLESVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQ 79

                          90       100
                  ....*....|....*....|....*.
gi 1720370339 231 ARCQKICDQWDNLGALTQKRREALER 256
Cdd:pfam00435  80 ERLEELNERWEQLLELAAERKQKLEE 105

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 267 LYLEYAKRAAPFNNWMEGAMEDLQDTFIVHTIEEIQGLTTAHEQFKATLpDADKERlaILGIHNEVSKIVQTYHVNmagt 346
Cdd:cd00176     1 KLQQFLRDADELEAWLSEKEELLSSTDYGDDLESVEALLKKHEALEAEL-AAHEER--VEALNELGEQLIEEGHPD---- 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 347 NPYTTITPQEINGKWDHVRQLVPRRDQALTEEHARQQHNERLRKqfgaqanvIGPWIQTKMEEIGRISIEMH-GTLEDQL 425
Cdd:cd00176    74 AEEIQERLEELNQRWEELRELAEERRQRLEEALDLQQFFRDADD--------LEQWLEEKEAALASEDLGKDlESVEELL 145

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1720370339 426 SHLRQYEKSIVNYKPKIDQLECDHQ-LIQEALIFDNKHTNYNMEHIRVGWEQLLTTIARTINEVENQI 492
Cdd:cd00176   146 KKHKELEEELEAHEPRLKSLNELAEeLLEEGHPDADEEIEEKLEELNERWEELLELAEERQKKLEEAL 213

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 507 EFRASFNHFDRDHSGTLGPEEFKACLISLGYDigndpqkktgmmdtddfraclismgynMGEAEFARIMSIVDPNRLGVV 586
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEG---------------------------LSEEEIDEMIREVDKDGDGKI 53

                          90
                  ....*....|
gi 1720370339 587 TFQAFIDFMS 596
Cdd:cd00051    54 DFEEFLELMA 63

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 497 AKGISQEQMNEFRASFNHFDRDHSGTLGPEEFKACLISLGYdigndpqkktgmmdtddfraclismgyNMGEAEFARIMS 576
Cdd:PTZ00184    2 ADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQ---------------------------NPTEAELQDMIN 54

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720370339 577 IVDPNRLGVVTFQAFIDFMSRETADTDTADQVMASFKILAGDKN-YITEDELR 628
Cdd:PTZ00184   55 EVDADGNGTIDFPEFLTLMARKMKDTDSEEEIKEAFKVFDRDGNgFISAAELR 107

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 391 QFGAQANVIGPWIQTKMEEIgriSIEMHG----TLEDQLSHLRQYEKSIVNYKPKIDQLECDHQLIQEALIFDNKHTNYN 466
Cdd:pfam00435   5 QFFRDADDLESWIEEKEALL---SSEDYGkdleSVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQER 81

                          90       100
                  ....*....|....*....|....
gi 1720370339 467 MEHIRVGWEQLLTTIARTINEVEN 490
Cdd:pfam00435  82 LEELNERWEQLLELAAERKQKLEE 105

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 1720370339 507 EFRASFNHFDRDHSGTLGPEEFKACLISLG 536
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

DNA repair ATPase RecN [Replication, recombination and repair];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 103 RLSNrpafmpSEgRMVSDINNAWGCLEQAEKGYEEWLLNEIRRLERLDHLAEKFRQ-KASIHEAWTDGKEA------MLR 175
Cdd:COG0497   217 RLSN------AE-KLREALQEALEALSGGEGGALDLLGQALRALERLAEYDPSLAElAERLESALIELEEAaselrrYLD 289

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 176 QKDYETATL-------SEIKALLKKHEAFESDLAAHQDRveqiaaIAQELNELDYYDS--PSVNARCQKICDQWDNLG-A 245
Cdd:COG0497   290 SLEFDPERLeeveerlALLRRLARKYGVTVEELLAYAEE------LRAELAELENSDErlEELEAELAEAEAELLEAAeK 363

                         170       180
                  ....*....|....*....|....*....
gi 1720370339 246 LTQKRREALERTEKLLET-IDQLYLEYAK 273
Cdd:COG0497   364 LSAARKKAAKKLEKAVTAeLADLGMPNAR 392

Ca2+ insensitive EF hand; EF hands are helix-loop-helix binding motifs involved in the regulation of many cellular processes. EF hands usually bind to Ca2+ ions which causes a major conformational change that allows the protein to interact with its designated targets. This domain corresponds to an EF hand which has partially or entirely lost its calcium-binding properties. The calcium insensitive EF hand is still able to mediate protein-protein recognition.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1720370339 601 DTDTADQVMASFKILAGDKNYITEDELRRELPPDQAEYCIARMAPYAGP--DSVPGALDYMSFSTALYG 667
Cdd:pfam08726   1 DTDTAEQVEASFRALAGGKPYVTEEDLRRELTPDQAEYCIARMPPYSGPdgDSVPGAYDYVSFSEALFG 69

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 151 HLAEKFRQKASIHEAWTDGKEAMLRQKDYETaTLSEIKALLKKHEAFESDLAAHQDRVEQIAAIAQELNELDYYDSPSVN 230
Cdd:pfam00435   1 LLLQQFFRDADDLESWIEEKEALLSSEDYGK-DLESVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQ 79

                          90       100
                  ....*....|....*....|....*.
gi 1720370339 231 ARCQKICDQWDNLGALTQKRREALER 256
Cdd:pfam00435  80 ERLEELNERWEQLLELAAERKQKLEE 105

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 267 LYLEYAKRAAPFNNWMEGAMEDLQDTFIVHTIEEIQGLTTAHEQFKATLpDADKERlaILGIHNEVSKIVQTYHVNmagt 346
Cdd:cd00176     1 KLQQFLRDADELEAWLSEKEELLSSTDYGDDLESVEALLKKHEALEAEL-AAHEER--VEALNELGEQLIEEGHPD---- 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 347 NPYTTITPQEINGKWDHVRQLVPRRDQALTEEHARQQHNERLRKqfgaqanvIGPWIQTKMEEIGRISIEMH-GTLEDQL 425
Cdd:cd00176    74 AEEIQERLEELNQRWEELRELAEERRQRLEEALDLQQFFRDADD--------LEQWLEEKEAALASEDLGKDlESVEELL 145

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1720370339 426 SHLRQYEKSIVNYKPKIDQLECDHQ-LIQEALIFDNKHTNYNMEHIRVGWEQLLTTIARTINEVENQI 492
Cdd:cd00176   146 KKHKELEEELEAHEPRLKSLNELAEeLLEEGHPDADEEIEEKLEELNERWEELLELAEERQKKLEEAL 213

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 266 QLYLEYAKRAAPFNNWMEGAMEDLQDTFIVHTIEEIQGLTTAHEQFKATLPDADKERLAIlgihNEVSKIVQTYHVNmag 345
Cdd:pfam00435   1 LLLQQFFRDADDLESWIEEKEALLSSEDYGKDLESVQALLKKHKALEAELAAHQDRVEAL----NELAEKLIDEGHY--- 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1720370339 346 TNPYTTITPQEINGKWDHVRQLVPRRDQALTE 377
Cdd:pfam00435  74 ASEEIQERLEELNERWEQLLELAAERKQKLEE 105

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339  31 QLMEDYEKLASDLLEWIRRTIPWLENRVPENTMHAMQQKLedfRDYRRLHKPPKVQEKCQLEInfNTLQTKLrLSNRPAF 110
Cdd:pfam00435   1 LLLQQFFRDADDLESWIEEKEALLSSEDYGKDLESVQALL---KKHKALEAELAAHQDRVEAL--NELAEKL-IDEGHYA 74

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1720370339 111 MPSEGRMVSDINNAWGCLEQAEKGYEEWLLN 141
Cdd:pfam00435  75 SEEIQERLEELNERWEQLLELAAERKQKLEE 105

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 499 GISQEQMNEFRASFNHFDRDHSGTLGPEEFKACLISLGYDIGNDPQKK---------TGMMDTDDFracLISMGYNMGE- 568
Cdd:PTZ00183   10 GLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQmiadvdkdgSGKIDFEEF---LDIMTKKLGEr 86

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1720370339 569 ---AEFARIMSIVDPNRLGVVTFQAfIDFMSRETAD--TDTADQVMASFKILAGDKNyITEDELRR 629
Cdd:PTZ00183   87 dprEEILKAFRLFDDDKTGKISLKN-LKRVAKELGEtiTDEELQEMIDEADRNGDGE-ISEEEFYR 150

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 512 FNHFDRDHSGTLGPEEFKACLISLG--------YDIGNDpqkktGMMDTDDFRACLISMGYNMGEAEFARIMSIVDPNRL 583
Cdd:cd16180    43 INMFDRDRSGTINFDEFVGLWKYIQdwrrlfrrFDRDRS-----GSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRR 117

                  ....*....
gi 1720370339 584 GVVTFQAFI 592
Cdd:cd16180   118 GSISFDDFV 126

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 391 QFGAQANVIGPWIQTKMEEIgriSIEMHG----TLEDQLSHLRQYEKSIVNYKPKIDQLECDHQLIQEALIFDNKHTNYN 466
Cdd:pfam00435   5 QFFRDADDLESWIEEKEALL---SSEDYGkdleSVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQER 81

                          90       100
                  ....*....|....*....|....
gi 1720370339 467 MEHIRVGWEQLLTTIARTINEVEN 490
Cdd:pfam00435  82 LEELNERWEQLLELAAERKQKLEE 105

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 505 MNEFRASFNHFDRDHSGTLGPEEFKACLISLGYDIgnDPQ---------KKTGMMDTDDFRACLISMgyNMGEAEFARim 575
Cdd:cd16181    69 LNQWKTTFMQYDRDRSGTVEPQELQQAIRSFGYNL--SPQalnvivkrySKNGRITFDDFVACAVRL--RALTDRFRR-- 142

                          90       100
                  ....*....|....*....|.
gi 1720370339 576 siVDPNRLGVVTFQaFIDFMS 596
Cdd:cd16181   143 --RDTQQNGTATFQ-YDDFIQ 160

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 516 DRDHSGTLGPEEFKACLISLG--------YDIGndpqkKTGMMDTDDFRACLISMGYNMGEAEFARIM---SivdpNRLG 584
Cdd:cd16196    51 DVDRSGKLGFEEFKKLWEDLRswkrvfklFDTD-----GSGSFSSFELRNALNSAGFRLSNATLNALVlryS----NKDG 121

                          90
                  ....*....|...
gi 1720370339 585 VVTFQAFIDFMSR 597
Cdd:cd16196   122 RISFDDFIMCAVK 134

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1720370339 509 RASFNHFDRDHSGTLGPEEFKACLISLGYDIGNDPQ--------KKTGMMDTDDFRACLISM 562
Cdd:cd16182    75 QAIFKKFDTDRSGTLSSYELRKALESAGFHLSNKVLqalvlryaDSTGRITFEDFVSCLVRL 136

Penta-EF hand, calcium binding motifs, found in sorcin; Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 505 MNEFRASFNHFDRDHSGTLGPEEFKACLISLGYDIgnDPQ---------KKTGMMDTDDFRACLISMgYNMGEAeFARim 575
Cdd:cd16187    69 LNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRL--SPQavnsiakrySTNGKITFDDYIACCVKL-RALTDS-FRR-- 142

                          90       100
                  ....*....|....*....|
gi 1720370339 576 siVDPNRLGVVTFQaFIDFM 595
Cdd:cd16187   143 --RDTSQQGVVNFP-YDDFI 159

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 503 EQMNEF----RASFNHFDRDHSGTLGPEEFKACLISLGYdiGNDPQ-----------KKTGMMDTDDFraclISMGYNMG 567
Cdd:cd16185    59 AALHQFlsnmQNGFEQRDTSRSGRLDANEVHEALAASGF--QLDPPafqalfrkfdpDRGGSLGFDDY----IELCIFLA 132

                          90       100
                  ....*....|....*....|.
gi 1720370339 568 EAEfaRIMSIVDPNRLGVVTF 588
Cdd:cd16185   133 SAR--NLFQAFDRQRTGRVTL 151

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720370339 505 MNEFRASFNHFDRDHSGTLGPEEFKACLISLGYDIGNDP--------QKKTGMMDTDDFRACLI 560
Cdd:cd15897    69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTydiiirryDRGRGNIDFDDFIQCCV 132

Penta-EF hand, calcium binding motifs, found in grancalcin; Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It displays a Ca2+-dependent translocation to granules and plasma membrane upon neutrophil activation, suggesting roles in granule-membrane fusion and degranulation of neutrophils. It may also play a role in the regulation of vesicle/granule exocytosis through the reversible binding of secretory vesicles and plasma membranes upon the presence of calcium. Moreover, GCA is involved in inflammation, as well as in the process of adhesion of neutrophils to fibronectin. It plays a key role in leukocyte-specific functions that are responsible for host defense, and affects the function of integrin receptors on immune cells through binding to L-plastin in the absence of calcium. Furthermore, GCA can strongly interact with sorcin to form a heterodimer, and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1720370339 505 MNEFRASFNHFDRDHSGTLGPEEFKACLISLGYDIgnDPQ---------KKTGMMDTDDFRACLISM 562
Cdd:cd16186    69 LNAWKQNFMTVDQDRSGTVEPHELRQAIGAMGYRL--SPQtlttivkrySKNGRIYFDDYVACCVKL 133

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720370339 546 KTGMMDTDDFRACLISMGYN-MGEAEFARIMSIVDPNRLGVVTFQAFIDFMSRE 598
Cdd:pfam13833   1 EKGVITREELKRALALLGLKdLSEDEVDILFREFDTDGDGYISFDEFCVLLERR 54

DNA repair ATPase RecN [Replication, recombination and repair];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 103 RLSNrpafmpSEgRMVSDINNAWGCLEQAEKGYEEWLLNEIRRLERLDHLAEKFRQ-KASIHEAWTDGKEA------MLR 175
Cdd:COG0497   217 RLSN------AE-KLREALQEALEALSGGEGGALDLLGQALRALERLAEYDPSLAElAERLESALIELEEAaselrrYLD 289

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720370339 176 QKDYETATL-------SEIKALLKKHEAFESDLAAHQDRveqiaaIAQELNELDYYDS--PSVNARCQKICDQWDNLG-A 245
Cdd:COG0497   290 SLEFDPERLeeveerlALLRRLARKYGVTVEELLAYAEE------LRAELAELENSDErlEELEAELAEAEAELLEAAeK 363

                         170       180
                  ....*....|....*....|....*....
gi 1720370339 246 LTQKRREALERTEKLLET-IDQLYLEYAK 273
Cdd:COG0497   364 LSAARKKAAKKLEKAVTAeLADLGMPNAR 392