Peptidase associated domain: C-terminal domain of M14 N/E carboxypeptidase; putative folding, regulation, or interaction domain; This domain is found C-terminal to the M14 carboxypeptidase (CP) N/E subfamily containing zinc-binding enzymes that hydrolyze single C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. The N/E subfamily includes enzymatically active members (carboxypeptidase N, E, M, D, and Z), as well as non-active members (carboxypeptidase-like protein 1, -2, aortic CP-like protein, and adipocyte enhancer binding protein-1) which lack the critical active site and substrate-binding residues considered necessary for activity. The active N/E enzymes fulfill a variety of cellular functions, including prohormone processing, regulation of peptide hormone activity, alteration of protein-protein or protein-cell interactions and transcriptional regulation. For M14 CPs, it has been suggested that this domain may assist in folding of the CP domain, regulate enzyme activity, or be involved in interactions with other proteins or with membranes; for carboxypeptidase M, it may interact with the bradykinin 1 receptor at the cell surface. This domain may also be found in other peptidase families.

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                 ....*....|....*....|....*....|....*....|....*....
gi 221044894   6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQKFHVPLVL 54
Cdd:cd05822   53 AQLAAGTYKLTFDTGAYFAARGQESFYPEVEVRFTITDPTEHYHVPLLL 101

HIUase (5-hydroxyisourate hydrolase) catalyzes the second step in a three-step ureide pathway in which 5-hydroxyisourate (HIU), a product of the uricase (urate oxidase) reaction, is hydrolyzed to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU). HIUase has high sequence similarity with transthyretins and is a member of the transthyretin-like protein (TLP) family. HIUase is distinguished from transthyretins by a conserved signature motif at its C-terminus that forms part of the active site. In HIUase, this motif is YRGS, while transthyretins have a conserved TAVV sequence in the same location. Most HIUases are cytosolic but in plants and slime molds, they are peroxisomal based on the presence of N-terminal periplasmic localization sequences. HIUase forms a homotetramer with each subunit consisting of eight beta-strands arranged in two sheets and a short alpha-helix. The central channel of the tetramer contains two independent binding sites, each located between a pair of subunits.

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                 ....*....|....*....|....*....|....*....|....*....
gi 221044894   6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQKFHVPLVL 54
Cdd:cd05822   53 AQLAAGTYKLTFDTGAYFAARGQESFYPEVEVRFTITDPTEHYHVPLLL 101

hydroxyisourate hydrolase; Members of this family, hydroxyisourate hydrolase, represent a distinct clade of transthyretin-related proteins. Bacterial members typically are encoded next to ureidoglycolate hydrolase and often near either xanthine dehydrogenase or xanthine/uracil permease genes and have been demonstrated to have hydroxyisourate hydrolase activity. In eukaryotes, a clade separate from the transthyretins (a family of thyroid-hormone binding proteins) has also been shown to have HIU hydrolase activity in urate catabolizing organisms. Transthyretin, then, would appear to be the recently diverged paralog of the more ancient HIUH family. [Purines, pyrimidines, nucleosides, and nucleotides, Other]

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                  ....*....|....*....|....*....|....*....|....*....
gi 221044894    6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQKFHVPLVL 54
Cdd:TIGR02962  53 EDLAPGIYKLRFDTGDYFAARGVESFYPEVEVVFTIADPGQHYHVPLLL 101

hydroxyisourate hydrolase; Provisional

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                 ....*....|....*....|....*....|....*....|....*.
gi 221044894   9 KAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQKFHVPLVL 54
Cdd:PRK15036  81 TTGDYRVVFKTGDYFKKQNLESFFPEIPVEFHINKVNEHYHVPLLL 126

HIUase (5-hydroxyisourate hydrolase) catalyzes the second step in a three-step ureide pathway in which 5-hydroxyisourate (HIU), a product of the uricase (urate oxidase) reaction, is hydrolyzed to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU). HIUase has high sequence similarity with transthyretins and is a member of the transthyretin-like protein (TLP) family. HIUase is distinguished from transthyretins by a conserved signature motif at its C-terminus that forms part of the active site. In HIUase, this motif is YRGS, while transthyretins have a conserved TAVV sequence in the same location. Most HIUases are cytosolic but in plants and slime molds, they are peroxisomal based on the presence of N-terminal periplasmic localization sequences. HIUase forms a homotetramer with each subunit consisting of eight beta-strands arranged in two sheets and a short alpha-helix. The central channel of the tetramer contains two independent binding sites, each located between a pair of subunits.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 221044894   6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQKFHVPLVL 54
Cdd:cd05822   53 AQLAAGTYKLTFDTGAYFAARGQESFYPEVEVRFTITDPTEHYHVPLLL 101

hydroxyisourate hydrolase; Members of this family, hydroxyisourate hydrolase, represent a distinct clade of transthyretin-related proteins. Bacterial members typically are encoded next to ureidoglycolate hydrolase and often near either xanthine dehydrogenase or xanthine/uracil permease genes and have been demonstrated to have hydroxyisourate hydrolase activity. In eukaryotes, a clade separate from the transthyretins (a family of thyroid-hormone binding proteins) has also been shown to have HIU hydrolase activity in urate catabolizing organisms. Transthyretin, then, would appear to be the recently diverged paralog of the more ancient HIUH family. [Purines, pyrimidines, nucleosides, and nucleotides, Other]

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 221044894    6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQKFHVPLVL 54
Cdd:TIGR02962  53 EDLAPGIYKLRFDTGDYFAARGVESFYPEVEVVFTIADPGQHYHVPLLL 101

Transthyretin_like. This domain is present in the transthyretin-like protein (TLP) family which includes transthyretin (TTR) and a transthyretin-related protein called 5-hydroxyisourate hydrolase (HIUase). TTR and HIUase are homotetrameric proteins with each subunit consisting of eight beta-strands arranged in two sheets and a short alpha-helix. The central channel of the tetramer contains two independent binding sites, each located between a pair of subunits. TTR transports thyroid hormones and retinol in the blood serum of vertebrates while HIUase catalyzes the second step in a three-step ureide pathway. TTRs are highly conserved and found only in vertebrates while the HIUases are found in a wide range of bacterial, plant, fungal, slime mold and vertebrate organisms.

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                 ....*....|....*....|....*....|....*....|....*....|
gi 221044894   6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTIT-SKAQKFHVPLVL 54
Cdd:cd05469   53 EEF*AGVYRVEFDTKSYWKALGITPFHEYAEVVFTANdSGHRHYTIALLL 102

Transthyretin (TTR) is a 55 kDa protein responsible for the transport of thyroid hormones and retinol in vertebrates. TTR distributes the two thyroid hormones T3 (3,5,3'-triiodo-L-thyronine) and T4 (Thyroxin, or 3,5,3',5'-tetraiodo-L-thyronine), as well as retinol (vitamin A) through the formation of a macromolecular complex that includes each of these as well as retinol-binding protein. Misfolded forms of TTR are implicated in the amyloid diseases familial amyloidotic polyneuropathy and senile systemic amyloidosis. TTR forms a homotetramer with each subunit consisting of eight beta-strands arranged in two sheets and a short alpha-helix. The central channel of the tetramer contains two independent binding sites, each located between a pair of subunits, which differ in their ligand binding affinity. A negative cooperativity has been observed for the binding of T4 and other TTR ligands. A fraction of plasma TTR is carried in high density lipoproteins by binding to apolipoprotein AI (apoA-I). TTR is able to proteolytically process apoA-I by cleaving its C-terminus; therefore TTR has protease activity in addition to its function in protein transport.

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                 ....*....|....*....|....*....|....*....|....*....|
gi 221044894   6 DQMKAGTYKLTFDTEGYWRKRGQESFYPHVEVVLTITSKAQK-FHVPLVL 54
Cdd:cd05821   59 EQFTEGVYKVEFDTKAYWKKLGISPFHEYAEVVFTANDSGHRhYTIAALL 108