Cis and trans actions of the cholinesterase-like domain within the thyroglobulin dimer.

Torna indietro

Abstract

Thyroglobulin (Tg; precursor for thyroid hormone synthesis) is a large secreted glycoprotein comprised of upstream regions I-II-III, followed by the ~570 residue cholinesterase-like (ChEL) domain. ChEL has two identified functions: 1) homodimerization, and 2) binding to I-II-III that facilitates I-II-III oxidative maturation required for intracellular protein transport. Like its homologs in the acetylcholinesterase (AChE) family, ChEL possesses two carboxyl-terminal alpha helices. We find that a Tg-AChE chimera (swapping AChE in place of ChEL) allows for dimerization with monomeric AChE, proving exposure of the carboxyl-terminal helices within the larger context of Tg. Further, we establish that perturbing trans-helical interaction blocks homodimerization of the Tg ChEL domain. Additionally, ChEL can associate with neuroligins (a related family of cholinesterase-like proteins), demonstrating potential for Tg cross-dimerization between non-identical partners. Indeed, when mutant rdw-Tg (Tg-G2298R, defective for protein secretion) is co-expressed with wild-type Tg, the two proteins cross-dimerize and secretion of rdw-Tg is partially restored. Moreover, we find that AChE and soluble neuroligins also can bind to the upstream Tg regions I-II-III; however, they cannot rescue secretion because they cannot facilitate oxidative maturation of I-II-III. The data highlight that specific properties of distinct Tg ChEL mutants may result in distinct patterns of Tg monomer folding, cross-dimerization with wild-type Tg, and variable secretion behavior in heterozygous patients.

Autore Pugliese

Tutti gli autori

  • Wang X. , Lee J. , Di Jeso B. , Treglia A.S. , Comoletti D. , Dubi N. , Taylor P. , Arvan P.

Titolo volume/Rivista

THE JOURNAL OF BIOLOGICAL CHEMISTRY

Anno di pubblicazione

2010

ISSN

0021-9258

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

Non Disponibile

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile