6cm1
From Proteopedia
MT1-MMP HPX Domain with Blade 2 Loop Bound to Nanodiscs
Structural highlights
Disease[APOA1_HUMAN] Defects in APOA1 are a cause of high density lipoprotein deficiency type 2 (HDLD2) [MIM:604091]; also known as familial hypoalphalipoproteinemia (FHA). Inheritance is autosomal dominant.[1] [2] Defects in APOA1 are a cause of the low HDL levels observed in high density lipoprotein deficiency type 1 (HDLD1) [MIM:205400]; also known as analphalipoproteinemia or Tangier disease (TGD). HDLD1 is a recessive disorder characterized by the absence of plasma HDL, accumulation of cholesteryl esters, premature coronary artery disease, hepatosplenomegaly, recurrent peripheral neuropathy and progressive muscle wasting and weakness. In HDLD1 patients, ApoA-I fails to associate with HDL probably because of the faulty conversion of pro-ApoA-I molecules into mature chains, either due to a defect in the converting enzyme activity or a specific structural defect in Tangier ApoA-I.[3] [4] Note=A mutation in APOA1 is the cause of amyloid polyneuropathy-nephropathy Iowa type (AMYLIOWA); also known as amyloidosis van Allen type or familial amyloid polyneuropathy type III. AMYLIOWA is a hereditary generalized amyloidosis due to deposition of amyloid mainly constituted by apolipoprotein A1. The clinical picture is dominated by neuropathy in the early stages of the disease and nephropathy late in the course. Death is due in most cases to renal amyloidosis. Severe peptic ulcer disease can occurr in some and hearing loss is frequent. Cataracts is present in several, but vitreous opacities are not observed.[5] [6] [7] [8] Defects in APOA1 are a cause of amyloidosis type 8 (AMYL8) [MIM:105200]; also known as systemic non-neuropathic amyloidosis or Ostertag-type amyloidosis. AMYL8 is a hereditary generalized amyloidosis due to deposition of apolipoprotein A1, fibrinogen and lysozyme amyloids. Viscera are particularly affected. There is no involvement of the nervous system. Clinical features include renal amyloidosis resulting in nephrotic syndrome, arterial hypertension, hepatosplenomegaly, cholestasis, petechial skin rash.[9] [10] [11] Function[MMP14_HUMAN] Seems to specifically activate progelatinase A. May thus trigger invasion by tumor cells by activating progelatinase A on the tumor cell surface. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15.[12] [13] [APOA1_HUMAN] Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT). As part of the SPAP complex, activates spermatozoa motility.[14] Publication Abstract from PubMedCritical to migration of tumor cells and endothelial cells is the proteolytic attack of membrane type 1 matrix metalloproteinase (MT1-MMP) upon collagen, growth factors, and receptors at cell surfaces. Lipid bilayer interactions of the substrate-binding hemopexin-like (HPX) domain of MT1-MMP were investigated by paramagnetic nuclear magnetic resonance relaxation enhancements (PREs), fluorescence, and mutagenesis. The HPX domain binds bilayers by blades II and IV on opposite sides of its beta propeller fold. The EPGYPK sequence protruding from both blades inserts among phospholipid head groups in PRE-restrained molecular dynamics simulations. Bilayer binding to either blade II or IV exposes the CD44 binding site in blade I. Bilayer association with blade IV allows the collagen triple helix to bind without obstruction. Indeed, vesicles enhance proteolysis of collagen triple-helical substrates by the ectodomain of MT1-MMP. Hypothesized side-by-side MT1-MMP homodimerization would allow binding of bilayers, collagen, CD44, and head-to-tail oligomerization. MT1-MMP Binds Membranes by Opposite Tips of Its beta Propeller to Position It for Pericellular Proteolysis.,Marcink TC, Simoncic JA, An B, Knapinska AM, Fulcher YG, Akkaladevi N, Fields GB, Van Doren SR Structure. 2018 Nov 21. pii: S0969-2126(18)30369-1. doi:, 10.1016/j.str.2018.10.008. PMID:30471921[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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