Substrate specificity of transthyretin: identification of natural substrates in the nervous system

• Type: Article in International Scientific Journal
• Date: 2009

Authors

Marcia A Liz (Author) Other; Carolina E Fleming (Author) Other; Ana F Nunes (Author) Other; Maria R Almeida (Author) ICBAS; Fernando M Mar (Author) Other; Youngchool Choe (Author) Other; Charles S Craik (Author) Other; James C Powers (Author) Other; Matthew Bogyo (Author) Other; Monica M Sousa (Author) FEUP

Journal

Title: Biochemical Journal

Vol. 419

Pages: 467-474

ISSN: 0264-6021

Publisher: PORTLAND PRESS LTD

Indexing

ISI Web of Knowledge - 38 Citations

Scopus - 42 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-003-KS1

DOI: 10.1042/bj20082090

Abstract (EN): Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a protease, cleaving apoA-I (apolipoprotein A-I) after a phenylalanine residue. In the present study, we further investigated TTR substrate specificity. By using both P-diverse libraries and a library of phosphonate inhibitors, a TTR preference for a lysine residue in P1 was determined, suggesting that TTR might have a dual specificity and that, in addition to apoA-I, other TTR substrates might exist. Previous studies revealed that TTR is involved in the homoeostasis of the nervous system, as it participates in neuropeptide maturation and enhances nerve regeneration. We investigated whether TTR proteolytic activity is involved in these functions. Both wild-type TTR and TTRprot- (proteolytically inactivc TTR) had a similar effect in the expression of peptidylglycine alpha-amidating mono-oxygenase, the rate-limiting enzyme in neuropeptide amidation, excluding the involvement of TTR proteolytic activity in neuropeptide maturation. However, TTR was able to cleave amidated NPY (neuropeptide Y), probably contributing to the increased NPY levels reported in TTR-knockout mice. To assess the involvement of TTR proteolytic activity in axonal regeneration, neurite outgrowth of cells cultivated with wild-type TTR or TTRprot-, was measured. Cells grown with TTRprot- displayed decreased neurite length, thereby suggesting that TTR proteolytic activity is important for its function as a regeneration enhancer. By showing that TTR is able to cleave NPY and that its proteolytic activity affects axonal growth, the present study shows that TTR has natural substrates in the nervous system, establishing further its relevance in neurobiology.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8