Tài liệu Báo cáo khoa học: A functional polymorphism of apolipoprotein C1 detected by mass

A functional polymorphism of apolipoprotein C1 detected

by mass spectrometry

Matthew S. Wroblewski1

, Joshua T. Wilson-Grady1

, Michael B. Martinez1

, Raj S. Kasthuri2

,

Kenneth R. McMillan3

, Cristina Flood-Urdangarin4 and Gary L. Nelsestuen1

1 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA

2 Department of Medicine, University of Minnesota, Minneapolis, MN, USA

3 American Indian Community Development Corporation, Minneapolis, MN, USA

4 St Mary’s Health Clinics, St Paul, MN, USA

Apolipoprotein C1 (ApoC1) is a component of very￾low-density lipoproteins (VLDLs), intermediate classes,

and high-density lipoproteins (HDLs). It has several

potential functions. It helps to maintain HDL structure

and activates plasma lysolecithin acyltransferase. It is

also able to modulate the interaction of apolipoprotein

E with b-migrating VLDLs and inhibit binding of

b-VLDL to low-density lipoprotein receptor-related

protein [1,2]. It is implicated in regulation of several

lipase enzymes [3–5]. An N-terminal 38-residue form of

ApoC1 is able to inhibit cholesterol ester transferase

[6]. ApoC1 accounts for inhibition of cholesterol ester

transferase by HDL [7]. Thus, ApoC1 has a number of

potential functions that may be important in vivo.

Known variants of the ApoC1 gene are limited to un￾translated regions of the gene, synonymous mutations

of the coding sequence and a number of variants of the

intron regions of the gene (NCBI database for ApoC1).

An important functional variant is found in the promo￾ter region where complex factors [8,9] may link ApoC1

expression levels to familial dysbetalipoprotemia, car￾diovascular disease, and Alzheimer’s disease [10–12].

Overexpression of human ApoC1 in the mouse produ￾ces a hyperlipidemic condition [4,13] with possible

beneficial effects for diabetes [14,15]. Hyperlipidemia

may result from increased inhibition of b-VLDL bind￾ing to the receptor and reduced clearance of VLDLs

from the circulation. Variants of ApoC2 and ApoC3

have been linked to metabolic disease [16–18]. This

study reports the first case of a structural variant of

ApoC1 as well as some protein properties that suggest

the functional significance of this residue change. They

Keywords

apolipoprotein C1; mass spectrometry;

polymorphism; protein–lipid contact surface

Correspondence

G. L. Nelsestuen, 6–155 Jackson Hall,

321 Church St SE, Minneapolis, MN 55455,

USA

Fax: +612 625 2163

Tel: +612 624 3622

E-mail: [email protected]

(Received 7 July 2006, revised 16 August

2006, accepted 18 August 2006)

doi:10.1111/j.1742-4658.2006.05473.x

A survey of plasma proteins in approximately 1300 individuals by

MALDI-TOF MS resulted in identification of a structural polymorphism

of apolipoprotein C1 (ApoC1) that was found only in persons of American

Indian or Mexican ancestry. MS ⁄MS analysis revealed that the alteration

consisted of a T45S variation. The methyl group of T45 forms part of the

lipid-interacting surface of ApoC1. In agreement with an impact on lipid

contact, the S45 variant was more susceptible to N-terminal truncation by

dipeptidylpeptidase IV in vitro than was the T45 variant. The S45 protein

also displayed greater N-terminal truncation (loss of Thr-Pro) in vivo than

the T45 variant. The S45 variant also showed preferential distribution to

the very-low-density lipoprotein fraction than the T45 protein. These prop￾erties indicate a functional effect of the S45 variant and support a role for

residue 45 in lipid contact and lipid specificity. Further studies are needed

to determine the effects of the variant and its altered N-terminal truncation

on the metabolic functions of ApoC1.

Abbreviations

ApoC1, apolipoprotein C1; ApoC2, apolipoprotein C2; ApoC3-0, ApoC3 that does not contain a carbohydrate chain; ApoC3-1, ApoC3 with a

GalNAc-Gal-sialic acid carbohydrate chain; ApoC3-2, ApoC3 containing the carbohydrate of ApoC3-1 plus an additional sialic acid residue;

DPPase, dipeptidylpeptidase IV; HDL, high-density lipoprotein; TTr, transthyretin; VLDL, very-low-density lipoprotein.

FEBS Journal 273 (2006) 4707–4715 ª 2006 The Authors Journal compilation ª 2006 FEBS 4707