Tài liệu Báo cáo khoa học: SREBPs: protein interaction and SREBPs Ryuichiro Sato doc

MINIREVIEW

SREBPs: protein interaction and SREBPs

Ryuichiro Sato

Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan

Introduction

The sterol regulatory element-binding protein

(SREBP) family members SREBP-1 and SREBP-2

are localized on the endoplasmic reticulum (ER) as

membrane proteins after being synthesized. Once the

intracellular cholesterol level is decreased, the

SREBPs subsequently move in vesicles to the Golgi

complex, where they are processed sequentially by

two proteases. These cleavage steps release the

mature forms of SREBPs, which enter the nucleus

and activate genes related to cholesterol and fatty

acid metabolism [1,2]. In both the cytoplasm and

nucleus, SREBPs associate with a variety of proteins.

This interaction determines their intracellular translo￾cation and stability, and also regulates their activities

as transcriptional factors.

Protein interaction on the ER and in the

cytosol

SREBPs are localized on the ER membrane, associat￾ing with another ER membrane protein, SREBP cleav￾age-activating protein (SCAP) (Fig. 1). SCAP has two

distinct domains. The N-terminal domain has eight

transmembrane helices, which include the so-called ste￾rol-sensing domain. This domain resembles sequences

in three other proteins that are postulated to interact

with sterols: HMG-CoA reductase, the Niemann–Pick

C1 protein, and Patched [3]. The C-terminal domain of

SCAP contains five WD repeats, which are sequences

of 40 amino acids found in many proteins involved

in protein–protein interactions. The WD repeat

domain is the region of SCAP that forms a complex

with the C-terminal domain of SREBPs [4]. When cells

Keywords

ATF6; HNF-4; importin; LRH-1; PGC-1; S1P;

S2P; SCAP; SREBPs

Correspondence

R. Sato, Department of Applied Biological

Chemistry, Graduate School of Agricultural

and Life Sciences, The University of Tokyo,

Tokyo 113-8657, Japan

Fax: +81 3 5841 5136

Tel: +81 3 5841 8029

E-mail: [email protected]

(Received 6 August 2008, revised 22

October 2008, accepted 24 October

2008)

doi:10.1111/j.1742-4658.2008.06807.x

Sterol regulatory element-binding proteins (SREBPs) are tightly controlled

by various mechanisms, including intracellular localization, protein process￾ing, limited proteolysis, post-translational modifications and interaction

with associated proteins. Here, I review the regulatory mechanisms of

SREBP activity through the interaction with various kinds of protein.

Abbreviations

AFF6, activating transcription factor-6; ARC, activator-recruited co-factor; CBP, CREB-binding protein; ER, endoplasmic reticulum; HNF-4,

hepatocyte nuclear factor-4; LDL, low-density lipoprotein; LRH-1, liver receptor homolog-1; PEPCK, phosphoenolpyruvate carboxykinase;

PGC-1, peroxisome proliferator-activated receptor-c coactivator-1; S1P, site 1 protease; S2P, site 2 protease; SCAP, SREBP cleavage￾activating protein; SREBP, sterol regulatory element-binding protein; SUMO, small ubiquitin-like modifier.

622 FEBS Journal 276 (2009) 622–627 ª 2008 The Author Journal compilation ª 2008 FEBS