Solution structures, dynamics, and lipid-binding of the sterile α-motif domain of the deleted in liver cancer 2

Hongyan Li, King Leung Fung, Dong Yan Jin, Stephen S.M. Chung, Yick Pang Ching, Irene Oi Lin Ng, Kong Hung Sze, Chi Bun Ko, Hongzhe Sun

Research output: Journal article publicationJournal articleAcademic researchpeer-review

29 Citations (Scopus)

Abstract

The deleted in liver cancer 2 (DLC2) is a tumor suppressor gene, frequently found to be underexpressed in hepatocellular carcinoma. DLC2 is a multidomain protein containing a sterile α-motif (SARI) domain, a GTPase-activating protein (GAP) domain, and a lipid-binding StAR-related lipid-transfer (START) domain. The SAM domain of DLC2, DLC2-SAM, exhibits a low level of sequence homology (15-30%) with other SAM domains, and appears to be the prototype of a new subfamily of SAM domains found in DLC2-related proteins. In the present study, we have determined the three-dimensional solution structure of DLC2-SAM using NMR methods together with molecular dynamics simulated annealing. In addition, we performed a backbone dynamics study. The DLC2-SAM packed as a unique four α-helical bundle stabilized by interhelix hydrophobic interactions. The arrangement of the four helices is distinct from all other known SAM domains. In contrast to some members of the SAM domain family which form either dinners or oligomers, both biochemical analyses and rotational correlation time (τc) measured by backbone15N relaxation experiments indicated that DLC2-SAM exists as a monomer in solution. The interaction of DLC2-SAM domain with sodium dodecyl sulfate (SDS) micelles and 1,2-dimyristoyl-sn-glycerol-3-phosphatidylglycerol (DMPG) phospholipids was examined by CD and NMR spectroscopic techniques. The DLC2-SAM exhibits membrane binding properties accompanied by minor loss of the secondary structure of the protein. Deletion studies showed that the self-association of DLC2 in vivo does not require SARI domain, instead, a protein domain consisting of residues 120-672 mediates the self-association of DLC2.
Original languageEnglish
Pages (from-to)1154-1166
Number of pages13
JournalProteins: Structure, Function and Genetics
Volume67
Issue number4
DOIs
Publication statusPublished - 1 Jun 2007
Externally publishedYes

Keywords

  • Deleted in liver cancer 2
  • Lipid-binding
  • NMR
  • Sterile α-motif (SAM)
  • Structures

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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