The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle.

Jamie J Kwan,Logan W Donaldson

doi:10.1186/1472-6807-7-34

Abstract

BackgroundThe tumor suppressor DLC2 (Deleted in Liver Cancer -2) participates in cell signaling at the mitochondrial membrane. DLC2 is characterized by a SAM (sterile alpha motif) domain, a Rho GTPase activating protein (GAP) domain, and a START lipid transfer domain.ResultsTowards understanding the function of DLC2, we have solved the NMR solution structure of the SAM domain. The DLC2-SAM domain structure reveals an atypical four-helix composition that is distinct from the five-helix SAM domain structures that have been determined to date. From structural alignments, helix 3 of the canonical SAM domain appears to be replaced by shorter, extended secondary structure that follows a similar path. Another difference is demonstrated by helices 1 and 2 that form a helical hairpin that is situated approximately parallel to the canonical helix 5.ConclusionThe DLC2-SAM domain adopts a structure that is topologically more similar to an anti-parallel four-helix bundle than a canonical SAM domain. This alternate topology may allow the DLC2-SAM domain to interact with a novel set of ligands.

Highlights

The tumor suppressor DLC2 (Deleted in Liver Cancer -2) participates in cell signaling at the mitochondrial membrane
Towards determining its functional role, we present the structure of the murine DLC2-Sterile Alpha Motif (SAM) domain solved using nuclear magnetic resonance (NMR) methods
The murine DLC2-SAM domain is located near the N-terminus of the protein with boundaries conspicuously defined by exons 2–4

Summary

Introduction

The tumor suppressor DLC2 (Deleted in Liver Cancer -2) participates in cell signaling at the mitochondrial membrane. Many tumors demonstrate a characteristic, non-random deletion of chromosomal material, termed loss of heterozygosity (LOH). From molecular genetics studies, Deleted in liver cancer-1 (DLC1) [1] and a closely related gene, DLC2 [2] were discovered at two distinct chromosomal loci known to be sensitive to LOH. Several studies suggest that DLC1 and DLC2 are tumor suppressors involved in the progression of a wide range of cancers [3]. Reintroduction of DLC1 suppresses proliferation of breast carcinoma [4] and hepatoma cells [5] and prevents the formation of tumors in nude mice. Expression of DLC2 prevents the formation of Ras induced foci in NIH3T3 cells [2]. DLC1 appears to be downregulated by promoter methylation [6]

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