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2011 ; 32
(2
): 127-43
Nephropedia Template TP
gab.com Text
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Twit Text #
English Wikipedia
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
#MMPMID21280145
Parkin JD
; San Antonio JD
; Pedchenko V
; Hudson B
; Jensen ST
; Savige J
Hum Mutat
2011[Feb]; 32
(2
): 127-43
PMID21280145
show ga
Collagen IV is the major protein found in basement membranes. It comprises three
heterotrimers (?1?1?2, ?3?4?5, and ?5?5?6) 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 ?1 chain or integrins in the ?5 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.
|Amino Acid Sequence
[MESH]
|Basement Membrane/*metabolism
[MESH]
|Collagen Type IV/*chemistry/genetics/*metabolism
[MESH]