Abstract
Type IV collagen, which is present in all metazoan, exists as a family of six homologous alpha(IV) chains, alpha1-alpha6, in mammals. The six chains assemble into three different triple helical protomers and self-associate as three distinct networks. The network underlies all epithelia as a component of basement membranes, which play important roles in cell adhesion, growth, differentiation, tissue repair and molecular ultrafiltration. The specificity of both protomer and network assembly is governed by amino acid sequences of the C-terminal noncollagenous (NC1) domain of each chain. In this study, the structural basis for protomer and network assembly was investigated by determining the crystal structure of the ubiquitous [(alpha1)(2).alpha2](2) NC1 hexamer of bovine lens capsule basement membrane at 2.0 A resolution. The NC1 monomer folds into a novel tertiary structure. The (alpha1)(2).alpha2 trimer is organized through the unique three-dimensional domain swapping interactions. The differences in the primary sequences of the hypervariable region manifest in different secondary structures, which determine the chain specificity at the monomer-monomer interfaces. The trimer-trimer interface is stabilized by the extensive hydrophobic and hydrophilic interactions without a need for disulfide cross-linking.
Highlights
Type IV collagen, which is present in all metazoan, exists as a family of six homologous ␣(IV) chains, ␣1–␣ 6, in mammals
The structural basis for protomer and network assembly was investigated by determining the crystal structure of the ubiquitous [(␣1)2.␣2]2 NC1 hexamer of bovine lens capsule basement membrane at 2.0 Å resolution
Distinct protomers of type IV collagen are assembled through molecular recognition of the noncollagenous (NC1) domains [17, 18]
Summary
The chains associate first through a series of noncovalent interactions between the C-terminal noncollagenous domains, which provide correct alignment and registration for the nucleation of triple-helix formation [7,8,9,10,11] This early molecular recognition event is common for all types of collagen, which are assembled from highly homologous but genetically distinct procollagen chains [12]. The structural basis of the collagen IV network assembly with respect to generic interactions of the NC1 domain that govern the network assembly and the specific interactions that govern the selection of chains was investigated This was accomplished by crystallization of the ubiquitous [(␣1)2.␣2]2 NC1 hexamer, isolated from bovine lens capsule basement membrane (LBM), and determination of its threedimensional structure at 2.0 Å resolution
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