Structure of the substrate-binding b domain of the Protein disulfide isomerase-like protein of the testis

abstract: ...Protein Disulfide Isomerase-Like protein of the Testis (PDILT) is a testis-specific member of the PDI family. PDILT displays similar domain architecture to PDIA1, the founding member of this protein family, but lacks catalytic cysteines needed for oxidoreduction reactions. This suggests special importance of chaperone activity of PDILT, but how it recognizes misfolded protein substrates is unknown. Here, we report the high-resolution crystal structure of the b domain of human PDILT. The structure reveals a conserved hydrophobic pocket, which is likely a principal substrate-binding site in PDILT. In the crystal, this pocket is occupied by side chains of tyrosine and tryptophan residues from another PDILT molecule, suggesting a preference for binding exposed aromatic residues in protein substrates. The lack of interaction of the b domain with the P-domains of calreticulin-3 and calmegin hints at a novel way of interaction between testis-specific lectin chaperones and PDILT. Further studies of this recently discovered PDI member would help to understand the important role that PDILT plays in the differentiation and maturation of spermatozoids.

... 2014 4 4464 16 12 2013 10 03 2014 Copyright 2014, Macmillan Publishers Limited. All rights reserved 2014 Macmillan Publishers Limited. All rights reserved This work is licensed under a Creative Commons Attribution-NonCommercial-ShareALike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ Protein Disulfide Isomerase-Like protein of the Testis (PDILT) is a testis-specific member of the PDI family. PDILT displays similar domain architecture to PDIA1, the founding member of this protein family, but lacks catalytic cysteines needed for oxidoreduction reactions. This suggests special importance of chaperone activity of PDILT, but how it recognizes misfolded protein substrates is unknown. Here, we report the high-resolution crystal structure of the b domain of human PDILT. The structure reveals a conserved hydrophobic pocket, which is likely a principal substrate-binding site in PDILT. In the crystal, this pocket is occupied by side chains of tyrosine and tryptophan residues from another PDILT molecule, suggesting a preference for binding exposed aromatic residues in protein substrates. The lack of interaction of the b domain with the P-domains of calreticulin-3 and calmegin hints at a novel way of interaction between testis-specific lectin chaperones and PDILT. Further studies of this recently discovered PDI member would help to understand the important role that PDILT plays in the differentiation and maturation of spermatozoids. Protein disulfide isomerase-like protein of the testis (PDILT) is a member of the Protein Disulfide Isomerase (PDI) family, a family responsible for catalyzing formation of native disulfide bonds in the endoplasmic reticulum (ER). This multifunctional and diverse family consists of approximately 20 proteins, each containing at least one thioredoxin-like domain 1 . PDIA1, the founding member and the most studied protein in the PDI family, displays the abb xa domain architecture, where a and a are catalytic domains, b and b are non-catalytic, and x denotes a conserved linker ( Fig. 1a ). PDILT is a 67-kDa protein that resides exclusively in the ER of male germ cells. Only discovered a few years ago, PDILT is distinguished from other PDI members for its tissue specific distribution and the absence of typical catalytic motifs 2 . Full-length PDILT shares 27% of sequence identity with PDIA1, and the a domain is the most strongly conserved between these proteins with 48% identity 2 . However, PDILT differs from PDIA1 and other PDIs in several intriguing aspects. The most striking difference between PDIA1 and PDILT lies in the a and a domains. Instead of the classical redox-active CXXC motif, PDILT lacks the catalytic cysteines needed for oxidoreduction and instead possesses SKQS and SKKC motifs in the a and a domains, respectively ( Fig. 1a ). The SXXC motif, also present in TMX2, is highly conserved in PDILT among different species. This motif is also found strictly conserved among bacterial thioredoxin proteins, but its functional implications remain unknown 3 . The absence of catalytic cysteines suggests that PDILT primarily functions as a chaperone, one of the principal functions of PDIA1. PDIA1 directly binds to unfolded proteins via its b domain 4 . PDILT does not display oxidoreductase activity in vitro and interacts with the -somatostatin peptide and the BPTI protein in non-native conformation, so it is likely that PDILT operates as a folding assistant for

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Gene: PDILT - protein disulfide isomerase-like, testis expressed - (NCBI)

Protein : 4nwy

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