3hy5 | pdb_00003hy5
Crystal structure of CRALBP
Structural highlights
Disease[RLBP1_HUMAN] Defects in RLBP1 are a cause of retinitis pigmentosa autosomal recessive (ARRP) [MIM:268000]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.[1] Defects in RLBP1 are the cause of Bothnia retinal dystrophy (BRD) [MIM:607475]; also known as Vasterbotten dystrophy. Affected individuals show night blindness from early childhood with features consistent with retinitis punctata albescens and macular degeneration.[2] Defects in RLBP1 are the cause of rod-cone dystrophy Newfoundland (NFRCD) [MIM:607476]. NFRCD is a retinal dystrophy reminiscent of retinitis punctata albescens but with a substantially lower age at onset and more-rapid and distinctive progression. Rod-cone dystrophies results from initial loss of rod photoreceptors, later followed by cone photoreceptors loss.[3] Defects in RLBP1 are a cause of retinitis punctata albescens (RPA) [MIM:136880]. A rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments. Function[RLBP1_HUMAN] Soluble retinoid carrier essential the proper function of both rod and cone photoreceptors. Participates in the regeneration of active 11-cis-retinol and 11-cis-retinaldehyde, from the inactive 11-trans products of the rhodopsin photocycle and in the de novo synthesis of these retinoids from 11-trans metabolic precursors. The cycling of retinoids between photoreceptor and adjacent pigment epithelium cells is known as the 'visual cycle'.[4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCellular retinaldehyde-binding protein (CRALBP) is essential for mammalian vision by routing 11-cis-retinoids for the conversion of photobleached opsin molecules into photosensitive visual pigments. The arginine-to-tryptophan missense mutation in position 234 (R234W) in the human gene RLBP1 encoding CRALBP compromises visual pigment regeneration and is associated with Bothnia dystrophy. Here we report the crystal structures of both wild-type human CRALBP and of its mutant R234W as binary complexes complemented with the endogenous ligand 11-cis-retinal, at 3.0 and 1.7 A resolution, respectively. Our structural model of wild-type CRALBP locates R234 to a positively charged cleft at a distance of 15 A from the hydrophobic core sequestering 11-cis-retinal. The R234W structural model reveals burial of W234 and loss of dianion-binding interactions within the cleft with physiological implications for membrane docking. The burial of W234 is accompanied by a cascade of side-chain flips that effect the intrusion of the side-chain of I238 into the ligand-binding cavity. As consequence of the intrusion, R234W displays 5-fold increased resistance to light-induced photoisomerization relative to wild-type CRALBP, indicating tighter binding to 11-cis-retinal. Overall, our results reveal an unanticipated domino-like structural transition causing Bothnia-type retinal dystrophy by the impaired release of 11-cis-retinal from R234W. Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W.,He X, Lobsiger J, Stocker A Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18545-50. Epub 2009 Oct 21. PMID:19846785[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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