Comparative analysis of the noncollagenous NC1 domain of type IV collagen: Identification of structural features important for assembly, function, and pathogenesis

Abstract

Abstract Type IV collagen α1‐α6 chains have important roles in the assembly of basement membranes and are implicated in the pathogenesis of Goodpasture Syndrome, an autoimmune disorder, and Alport Syndrome, a hereditary renal disease. We report comparative sequence analyses and structural predictions of the noncollagenous C‐terminal globular NC1 domain (28 sequences). The inferred tree verified that type IV collagen sequences fall into two groups, α‐1‐like and α2‐like, and suggested that vertebrate α3/α4 sequences evolved before α1/α2 and α5/α6. About one fifth of NC1 residues were identified to confer either the α1 or α2 group‐specificity. These residues accumulate opposite Charge in subdomain B of α1 (positive) and α2 (negative) sequences and may play a role in the stoichiometric chain selection upon type IV collagen assembly. Neural network secondary structure prediction on multiple aligned sequences revealed a subdomain core structure consisting of six hydrophobic β‐strands and one short α‐helix with a significant hydrophobic moment. The existence of opposite charges in the a‐helices may carry implications for intersubdomain interactions. The results provide a rationale for defining the epitope that binds Goodpasture autoantibodies and a framework for understanding how certain NC1 mutations may lead to Alport Syndrome. A search algorithm, based entirely on amino acid properties, yielded a possible similarity of NC1 to tissue inhibitor of metalloproteinases (TIMP) and prompted an investigation of a possible functional relationship. The results indicate that NC1 preparations decrease the activity of matrix metalloproteinases 2 and 3 (MMP‐2, MMP‐3) toward a peptide Substrate, though not to [14C]‐gelatin. We suggest that an ancestral NC1 may have been incorporated into type IV collagen as an evolutionarily mobile domain carrying Proteinase inhibitor function.

Keywords

Affiliated Institutions

• University of Kansas Medical Center US

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