3r2p
From Proteopedia
2.2 Angstrom Crystal Structure of C Terminal Truncated Human Apolipoprotein A-I Reveals the Assembly of HDL by Dimerization.
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[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.[12] Publication Abstract from PubMedApolipoprotein A-I (apoA-I) plays important structural and functional roles in plasma high-density lipoprotein (HDL) that is responsible for reverse cholesterol transport. However, a molecular understanding of HDL assembly and function remains enigmatic. The 2.2A crystal structure of Delta(185-243)apoA-I reported here shows that it forms a half circle dimer. The backbone of the dimer consists of two elongated antiparallel proline-kinked helices (5 AB tandem repeats). The N-terminal domain of each molecule forms a four-helix bundle with the helical C-terminal region of the symmetry related partner. The central region forms a flexible domain with two antiparallel helices connecting the bundles at each end. The two-domain, dimer structure based on helical repeats suggests the role of apoA-I in the formation of discoidal HDL particles. Furthermore, the structure suggests the possible interaction with lecithin-cholesterol acyltransferase (LCAT), and may shed light on the molecular details of the effect of the Milano, Paris and Fin mutations. Crystal structure of C-terminal truncated apolipoprotein A-I reveals the assembly of HDL by dimerization.,Mei X, Atkinson D J Biol Chem. 2011 Sep 13. PMID:21914797[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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