C4

C-terminal tandem repeated domain in type 4 procollagens

• SMART accession number: SM00111
• Description: Duplicated domain in C-terminus of type 4 collagens. Mutations in alpha-5 collagen IV are associated with X-linked Alport syndrome.
• Interpro abstract (IPR001442):

  This duplicated domain is present at the C-terminal of type 4 collagen, the major structural component of glomerular basement membranes (GMB) forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen. Mutations in alpha-5 collagen IV are associated with X-linked Alport syndrome.

  Collagens are major components of the extracellular matrices of all metazoan life and play crucial roles in developmental processes and tissue homeostasis. Collagens are composed of three polypeptide chains (alpha chains) that fold together to form the characteristic triple helical collagenous domain. Some types of triple helical protomers contain genetically identical alpha chains forming homotrimers, whereas others contain two or three different alpha chains forming heterotrimers. The sequences required to form a collagenous domain are Gly-X-Y repeats in which the X and Y positions are frequently proline and hydroxyproline. Glycine is required every third residue as it is the only amino acid small enough to pack into the central core of the triple helix. The triple helix-forming parts are surrounded by non-collagenous (NC) domains of variable sequence, size, and shape. Even if the triple helical parts represent the most striking feature of collagens, tissue specificity as well as defined binding of non-collagens seem to be encoded in the NC domains. The terminal NC domains are excised, modified, or incorporated directly into the final suprastructure, depending on protomer type and function [ (PUBMED:12539240) (PUBMED:1639194) ].

  Type IV collagen is one of the major constituents of basement membranes, a specialised form of extracellular matrix underlying epithelia that compartmentalises tissues and provides molecular signals for influencing cell behaviour. Each type IV chain contains a long triple-helical collagenous domain flanked by a short 7S domain of 25 residues and a globular non-collagenous NC1 domain of ~230 residues at the N and C terminus, respectively. In protomer assembly, the NC1 domains (monomers) of three chains interact, forming an NC1 trimer, to select and register chains for triple helix formation. In network assembly, the NC1 trimers of two protomers interact, forming a NC1 hexamer structure, to select and connect protomers [ (PUBMED:12011424) (PUBMED:11970952) (PUBMED:15299013) ].

  The collagen IV NC1 domain contains 12 cysteines, and all of them are involved in disulphide bonds. It folds into a tertiary structure with predominantly beta-strands. The collagen IV NC1 domain is composed of two similarly folded subdomains stabilised by 3 intrachain dissulphide bonds involving the following pairs: C1-C6, C2-C5, and C3-C4. Each subdomain represents a compact disulphide-stabilised triangular structure, from which a finger-like hairpin loop projects into an incompletely formed six-stranded beta-sheet of an adjacent subdomain of the same or of an adjacent chain clamping the subdomains tightly together [ (PUBMED:12011424) (PUBMED:11970952) (PUBMED:15299013) ].

• GO component: collagen trimer (GO:0005581)
• GO function: extracellular matrix structural constituent (GO:0005201)

There are 5781 C4 domains in 2900 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Tverskaya S, Bobrynina V, Tsalykova F, Ignatova M, Krasnopolskaya X, Evgrafov O
• Substitution of A1498D in noncollagen domain of a5(IV) collagen chain associated with adult-onset X-linked Alport syndrome.
• Hum Mutat. 1996; 7: 149-50

• Matsukura H, Butkowski RJ, Fish AJ
• The Goodpasture antigen: common epitopes in the globular domains of collagen IV.
• Nephron. 1993; 64: 532-9

To determine the nature of Goodpasture antibody-reactive epitopes on the globular domains of collagen IV [non collagenous (NC) domain], Goodpasture antigen was characterized by immunochemical and immunohistological techniques using affinity-purified (AP) Goodpasture autoantibodies. Affinity purification of Goodpasture autoantibodies toward alpha 1(IV), alpha 2(IV), and alpha 3(IV) NC domains was performed and revealed antigenic cross-reactivity with all alpha(IV) NC domain subunits, which was confirmed by inhibition ELISA. Since by immunofluorescent microscopy all 3 AP Goodpasture antibodies only stained the central portion (lamina densa) of bovine glomerular basement membrane, it appears that there are common epitopes reactive with Goodpasture autoantibodies present on alpha 1(IV) NC, alpha 2(IV) NC, and alpha 3(IV) NC domains.

• Pihlajaniemi T et al.
• cDNA clones coding for the pro-alpha1(IV) chain of human type IV procollagen reveal an unusual homology of amino acid sequences in two halves of the carboxyl-terminal domain.
• J Biol Chem. 1985; 260: 7681-7

We report the isolation and characterization of cDNA clones coding for part of the pro-alpha1(IV) chain of human type IV procollagen. A cDNA library was prepared from total RNA isolated from a cultured human tumor cell line, HT-1080, and screened with a cloned mouse cDNA coding for the pro-alpha1(IV) chain. The largest cDNA clone encoded for 185 amino acid residues of the -Gly-X-Y-sequence of the human pro-alpha1(IV) chain, all of the globular carboxyl-terminal domain, and the 3' noncoding region. The results provide the first complete sequence for the carboxyl-terminal globular portion of a type IV procollagen chain. A striking feature of the carboxyl-terminal globular domain was a homology between the first and second half of the structure. The homology involved all 12 cysteine residues, the spacing between the cysteine residues, and many adjacent amino acids. The results raised the possibility that evolution of the globular domain involved duplication of an ancestral sequence coding for about 100 amino acids, 6 of which were cysteine. The homology, however, was more apparent in the amino acid sequence than in the nucleotide sequence, and, therefore, the results suggested that the homology reflects selective pressure on the function of the protein more than conservation of the nucleotide sequences in the gene. The nucleotide sequences of the 3' noncoding region of the cDNAs contained four polyadenylation signals of AATAAA. Three or four of the polyadenylation signals were probably used in transcription, since one major and two minor smaller RNA species from human skin fibroblasts hydridized with the cDNAs. In further studies, sorted human chromosomes were used to locate the gene for the pro-alpha1(IV) chain on chromosome 13.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the C4 domain.

Protein	Disease
Collagen alpha-4(IV) chain (P53420) (SMART)	OMIM:120131: Alport syndrome, autosomal recessive OMIM:203780: Hematuria, familial benign
Collagen alpha-5(IV) chain (P29400) (SMART)	OMIM:303630: Alport syndrome OMIM:301050:
Collagen alpha-3(IV) chain (Q01955) (SMART)	OMIM:120070: Alport syndrome, autosomal recessive OMIM:203780:

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
33.33	map05222	Small cell lung cancer
33.33	map04512	ECM-receptor interaction
33.33	map04510	Focal adhesion

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with C4 domain which could be assigned to a KEGG orthologous group, and not all proteins containing C4 domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of C4 domains in PDB

PDB code	Title
1li1	The 1.9-A crystal structure of the noncollagenous (NC1) domain of human placenta collagen IV shows stabilization via a novel type of covalent Met-Lys cross-link
1m3d	Structure of Type IV Collagen NC1 Domains
1t60	Crystal structure of Type IV collagen NC1 domain from bovine lens capsule
1t61	crystal structure of collagen IV NC1 domain from placenta basement membrane

Links (links to other resources describing this domain)

• INTERPRO: IPR001442