Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W

He, Xiaoqin; Lobsiger, Joel; Stocker, Achim (2009). Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 106(44), pp. 18545-18550. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.0907454106

[img] Text
PNAS.STOCKER.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

Cellular 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

He, Xiaoqin and Stocker, Achim

ISSN:

0027-8424

Publisher:

National Academy of Sciences NAS

Funders:

[UNSPECIFIED] Berne University Research Foundation

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:20

Last Modified:

08 Jan 2015 23:06

Publisher DOI:

10.1073/pnas.0907454106

PubMed ID:

19846785

Web of Science ID:

000271429800026

BORIS DOI:

10.7892/boris.36097

URI:

https://boris.unibe.ch/id/eprint/36097 (FactScience: 203248)

Actions (login required)

Edit item Edit item
Provide Feedback