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J. Biol. Chem., Vol. 281, Issue 31, 21682-21689, August 4, 2006

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Productive Folding of Tyrosinase Ectodomain Is Controlled by the Transmembrane Anchor^*

Costin I. Popescu, Alina Mares, Livia Zdrentu, Nicole Zitzmann, Raymond A. Dwek¹, and Stefana M. Petrescu¹²

From the Institute of Biochemistry, Splaiul Independentei 296, 060031 Bucharest 17, Romania and Oxford Glycobiology Institute, Department of Biochemistry, South Parks Road, OX1 3QU Oxford, United Kingdom

Transmembrane domains (TMDs) are known as structural elements required for the insertion into the membrane of integral membrane proteins. We have provided here an example showing that the presence of the TMD is compulsory for the productive folding pathway of a membrane-anchored glycoprotein. Tyrosinase, a type I transmembrane protein whose insertion into the melanosomal membrane initiates melanin synthesis, is misfolded and degraded when expressed as a truncated polypeptide. We used constructs of tyrosinase ectodomain fused with chimeric TMDs or glycosylphosphatidylinositol anchor to gain insights into how the TMD enables the productive folding pathway of the ectodomain. We found that in contrast to the soluble constructs, the membrane-anchored chimeras fold into the native conformation, which allows their endoplasmic reticulum exit. They recruit calnexin to monitor their productive folding pathway characterized by the post-translational formation of buried disulfides. Lacking calnexin assistance, the truncated mutant is arrested in an unstable conformation bearing exposed disulfides. We showed that the transmembrane anchor of a protein may crucially, albeit indirectly, control the folding pathway of the ectodomain.

Received for publication, April 21, 2006 , and in revised form, May 31, 2006.

^* This work was supported by the Wellcome Trust (CRIG 064227). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Inst. of Biochemistry, Romanian Academy, Splaiul Independentei 296, 77700 Bucharest 17, Romania. Tel.: 4021-223-9069; Fax: 4021-223-9068; E-mail: stefana.petrescu{at}biochim.ro.

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