Publication Date:
2014-10-14
Description:
Sterols are essential biological molecules in the majority of life forms. Sterol reductases including Delta(14)-sterol reductase (C14SR, also known as TM7SF2), 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) reduce specific carbon-carbon double bonds of the sterol moiety using a reducing cofactor during sterol biosynthesis. Lamin B receptor (LBR), an integral inner nuclear membrane protein, also contains a functional C14SR domain. Here we report the crystal structure of a Delta(14)-sterol reductase (MaSR1) from the methanotrophic bacterium Methylomicrobium alcaliphilum 20Z (a homologue of human C14SR, LBR and DHCR7) with the cofactor NADPH. The enzyme contains ten transmembrane segments (TM1-10). Its catalytic domain comprises the carboxy-terminal half (containing TM6-10) and envelops two interconnected pockets, one of which faces the cytoplasm and houses NADPH, while the other one is accessible from the lipid bilayer. Comparison with a soluble steroid 5beta-reductase structure suggests that the reducing end of NADPH meets the sterol substrate at the juncture of the two pockets. A sterol reductase activity assay proves that MaSR1 can reduce the double bond of a cholesterol biosynthetic intermediate, demonstrating functional conservation to human C14SR. Therefore, our structure as a prototype of integral membrane sterol reductases provides molecular insight into mutations in DHCR7 and LBR for inborn human diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285568/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285568/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Xiaochun -- Roberti, Rita -- Blobel, Gunter -- P41 GM111244/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 1;517(7532):104-7. doi: 10.1038/nature13797. Epub 2014 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA. ; Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25307054" target="_blank"〉PubMed〈/a〉
Keywords:
Binding Sites
;
Catalytic Domain
;
Cell Membrane/*metabolism
;
Cholesterol/biosynthesis
;
Crystallography, X-Ray
;
Humans
;
Membrane Proteins/chemistry/metabolism
;
Methylococcaceae/*enzymology
;
Models, Molecular
;
NADP/chemistry/metabolism
;
Oxidoreductases/*chemistry/*metabolism
;
Oxidoreductases Acting on CH-CH Group Donors/chemistry/genetics/metabolism
;
Receptors, Cytoplasmic and Nuclear/chemistry/genetics
;
Sterols/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
