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Identification of putative in vivo substrates of calpain 3 by comparative proteomics of overexpressing transgenic and nontransgenic mice

Lookup NU author(s): Dr Louise VB Anderson, Emerita Professor Katherine Bushby

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Abstract

Calpain 3 (CAPN3) is a calcium-dependent protease, mutations in which cause limb girdle muscular dystrophy type 2A. To explore the physiological function of CAPN3, we compared the proteomes of transgenic mice that overexpress CAPN3 (CAPN3 Tg) and their nontransgenic (non-Tg) counterparts. We first examined known muscular dystrophy-related proteins to determine if overexpression of CAPN3 results in a change in their distribution or concentration. This analysis did not identify any known muscular dystrophy proteins as substrates of CAPN3. Next, we used a proteomic approach to compare and identify differentially represented proteins in 2-DE of CAPN3 Tg and non-Tg mice. LC-MS/MS analysis led to the identification of ten possible substrates for CAPN3, classified into two major functional categories: metabolic and myofibrillar. Myosin light chain 1 (MLC1) was focused upon because our previous studies suggested a role for CAPN3 in sarcomere remodeling. In this study, CAPN3 was shown to proteolyze MLC1 in vitro. These studies are the first to identify possible substrates for CAPN3 in an in vivo system and support a role for CAPN3 in sarcomere remodeling by cleavage of myofibrillar proteins such as MLC1. In addition, these data also suggest a role for CAPN3 in mitochondrial protein turnover. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.


Publication metadata

Author(s): Cohen N, Kudryashova E, Kramerova I, Anderson LVB, Beckmann JS, Bushby K, Spencer MJ

Publication type: Article

Publication status: Published

Journal: Proteomics

Year: 2006

Volume: 6

Issue: 22

Pages: 6075-6084

ISSN (print): 1615-9853

ISSN (electronic): 1615-9861

Publisher: Wiley - VCH Verlag GmbH & Co. KGaA

URL: http://dx.doi.org/10.1002/pmic.200600199

DOI: 10.1002/pmic.200600199

PubMed id: 17051641


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Funding

Funder referenceFunder name
AR48177NIAMS NIH HHS
R01 AR048177NIAMS NIH HHS
R01 AR048177-08NIAMS NIH HHS

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