Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Feb;32(2):127-43.
doi: 10.1002/humu.21401.

Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes

J Des Parkin  1 , James D San Antonio, Vadim Pedchenko, Billy Hudson, Shane T Jensen, Judy Savige
Affiliations
Review

Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes

J Des Parkin et al. Hum Mutat. 2011 Feb.

Abstract

Collagen IV is the major protein found in basement membranes. It comprises three heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that form distinct networks, and are responsible for membrane strength and integrity.We constructed linear maps of the collagen IV heterotrimers ("interactomes") that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype–phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin, and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection, and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases, and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example, for Von Hippel Lindau (VHL) protein in the α1 chain or integrins in the α5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms, and muscle Cramps [HANAC] syndrome, and early-onset Alport syndrome, respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets.

PubMed Disclaimer

Conflict of interest statement

The authors have declared no conflict of interest.

Figures

Figure 1
Figure 1
Linear protein maps of the a. α1α1α2; b. α3α4α5; and c. α5α5α6 heterotrimers of collagen IV. The protein sequences were derived and aligned as indicated in the text. The sequence is linear with alternating bands shown in green or white. Non-collagenous interruptions in the sequence are in blue. Cysteines are shown in orange and indicated by orange arrows. Binding sites are indicated on only one of the 2 α1 or α5 chains. Binding sites for laminin, nidogen, heparan sulfate proteoglycan and fibronectin were derived from rotary shadowing studies in EHS-derived collagen and are shown here on both the α1 and α2 chains but the locations are approximate. Otherwise binding sites were identified from binding motifs. Predicted sites have been identified from homology with known motifs. Underlined residues in the α1 chain are hydroxylated. Residues at the same location in the α2 chain are generally also hydroxylated. Asterisks indicate 3′ hydroxylation sites. Sequence variants are indicated above the wildtype. Non-pathogenic changes are shown in red and pathogenic variants in black (where phenotype is not characterised or is: for α1 chain – vascular stroke or porencephaly; for α3 and α4: TBMN; and for α5: X-linked Alport syndrome with adult onset renal failure) or green (for α1 chain – HANAC; α3 and α4: autosomal dominant Alport syndrome; and for α5 - X-linked Alport syndrome with juvenile onset renal failure. References are provided in the text.
Figure 1
Figure 1
Linear protein maps of the a. α1α1α2; b. α3α4α5; and c. α5α5α6 heterotrimers of collagen IV. The protein sequences were derived and aligned as indicated in the text. The sequence is linear with alternating bands shown in green or white. Non-collagenous interruptions in the sequence are in blue. Cysteines are shown in orange and indicated by orange arrows. Binding sites are indicated on only one of the 2 α1 or α5 chains. Binding sites for laminin, nidogen, heparan sulfate proteoglycan and fibronectin were derived from rotary shadowing studies in EHS-derived collagen and are shown here on both the α1 and α2 chains but the locations are approximate. Otherwise binding sites were identified from binding motifs. Predicted sites have been identified from homology with known motifs. Underlined residues in the α1 chain are hydroxylated. Residues at the same location in the α2 chain are generally also hydroxylated. Asterisks indicate 3′ hydroxylation sites. Sequence variants are indicated above the wildtype. Non-pathogenic changes are shown in red and pathogenic variants in black (where phenotype is not characterised or is: for α1 chain – vascular stroke or porencephaly; for α3 and α4: TBMN; and for α5: X-linked Alport syndrome with adult onset renal failure) or green (for α1 chain – HANAC; α3 and α4: autosomal dominant Alport syndrome; and for α5 - X-linked Alport syndrome with juvenile onset renal failure. References are provided in the text.
Figure 1
Figure 1
Linear protein maps of the a. α1α1α2; b. α3α4α5; and c. α5α5α6 heterotrimers of collagen IV. The protein sequences were derived and aligned as indicated in the text. The sequence is linear with alternating bands shown in green or white. Non-collagenous interruptions in the sequence are in blue. Cysteines are shown in orange and indicated by orange arrows. Binding sites are indicated on only one of the 2 α1 or α5 chains. Binding sites for laminin, nidogen, heparan sulfate proteoglycan and fibronectin were derived from rotary shadowing studies in EHS-derived collagen and are shown here on both the α1 and α2 chains but the locations are approximate. Otherwise binding sites were identified from binding motifs. Predicted sites have been identified from homology with known motifs. Underlined residues in the α1 chain are hydroxylated. Residues at the same location in the α2 chain are generally also hydroxylated. Asterisks indicate 3′ hydroxylation sites. Sequence variants are indicated above the wildtype. Non-pathogenic changes are shown in red and pathogenic variants in black (where phenotype is not characterised or is: for α1 chain – vascular stroke or porencephaly; for α3 and α4: TBMN; and for α5: X-linked Alport syndrome with adult onset renal failure) or green (for α1 chain – HANAC; α3 and α4: autosomal dominant Alport syndrome; and for α5 - X-linked Alport syndrome with juvenile onset renal failure. References are provided in the text.
Figure 2
Figure 2
A comparison of integrin and extracellular matrix binding sites for collagens I and IV. These diagrams demonstrate the periodicity of integrin and extracellular structural protein binding to the collagen I heterotrimer. On the collagen IV heterotrimers they demonstrate how integrin binding sites are distributed throughout the α1α1α2, α3α4α5 and α5α5α6 heterotrimers and the periodicity of extracellular matrix structural protein binding in the α1α1α2 heterotrimer of collagen IV.
Figure 2
Figure 2
A comparison of integrin and extracellular matrix binding sites for collagens I and IV. These diagrams demonstrate the periodicity of integrin and extracellular structural protein binding to the collagen I heterotrimer. On the collagen IV heterotrimers they demonstrate how integrin binding sites are distributed throughout the α1α1α2, α3α4α5 and α5α5α6 heterotrimers and the periodicity of extracellular matrix structural protein binding in the α1α1α2 heterotrimer of collagen IV.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alonso R, Llopis I, Flores C, Murgui A, Timoneda J. Different adhesins for type IV collagen on Candida albicans: identification of a lectin-like adhesin recognizing the 7S(IV) domain. Microbiol. 2001;147:1971–1981. - PubMed
    1. Ancsin JB, Kisilevsky R. Characterization of high affinity binding between laminin and the acute-phase protein, serum amyloid A. J Biol Chem. 1997;272(1):406–413. - PubMed
    1. Asada S, Koide T, Yasui H, Nagata K. Effect of HSP47 on prolyl 4-hydroxylation of collagen model peptides. Cell Struct Funct. 1999;24(4):187–196. - PubMed
    1. Aumailley M, Wiedemann H, Mann K, Timpl R. Binding of nidogen and the laminin-nidogen complex to basement-membrane collagen type-IV. E J Biochem. 1989;184(1):241–248. - PubMed
    1. Bago R, Pavelic J, Vlahovicek GM, Bosnar MH. Nm23-H1 Promotes Adhesion of CAL 27 Cells In Vitro. Mol Carcinogenesis. 2009;48(9):779–789. - PubMed

Publication types