Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum

Xiaochun Li, Rita Roberti, Gunter Blobel

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Sterols are essential biologicalmolecules in themajority of life forms. Sterol reductases including δ 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 δ 14-sterol reductase (MaSR1) from the methanotrophic bacterium Methylomicrobium alcaliphilum 20Z (a homologue of human C14SR, LBR and DHCR7) with the cofactorNADPH. The enzymecontains ten transmembrane segments (TM1-10). Its catalytic domain comprises the carboxy-terminal half (containingTM6-10) 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 5β-reductase structure3 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 humanC14SR. Therefore, our structure as a prototype of integral membrane sterol reductases providesmolecular insight intomutations inDHCR7 and LBR for inborn human diseases.

Original languageEnglish (US)
Pages (from-to)104-107
Number of pages4
JournalNature
Volume517
Issue number7532
DOIs
StatePublished - Jan 1 2015

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Sterols
Oxidoreductases
Membranes
NADP
Carbon
Desmosterol
Nuclear Envelope
Lipid Bilayers
Nuclear Proteins
Catalytic Domain
Membrane Proteins
Cytoplasm
Steroids
Cholesterol
Bacteria

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum. / Li, Xiaochun; Roberti, Rita; Blobel, Gunter.

In: Nature, Vol. 517, No. 7532, 01.01.2015, p. 104-107.

Research output: Contribution to journalArticle

Li, Xiaochun ; Roberti, Rita ; Blobel, Gunter. / Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum. In: Nature. 2015 ; Vol. 517, No. 7532. pp. 104-107.
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