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Biochemistry. 2009 Jan 20;48(2):254-63. doi: 10.1021/bi801483u.

The SH3 domain of alphaII spectrin is a target for the Fanconi anemia protein, FANCG.

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Department of Pathology and Laboratory Medicine, UMDNJNew Jersey Medical School and Graduate School of Biomedical Sciences, Newark, New Jersey 07103, USA.


The structural protein nonerythroid alpha spectrin (alphaIISp) plays a role in the repair of DNA interstrand cross-links and is deficient in cells from patients with Fanconi anemia (FA), in which there is a defect in ability to repair such cross-links. We have proposed a model in which alphaIISp, whose stability is dependent on FA proteins, acts as a scaffold to aid in recruitment of repair proteins to sites of damage. In order to get a clearer understanding of the proposed role of FA proteins in maintaining stability of alphaIISp, yeast two-hybrid analysis was carried out to determine whether FA proteins directly interact with alphaIISp and, if so, to map the sites of interaction. Four overlapping regions of alphaIISp were constructed. FANCG interacted with one of these regions and specifically with the SH3 domain in this region of alphaIISp. The site of interaction in FANCG was mapped to a motif that binds to SH3 domains and contains a consensus sequence with preference for the SH3 domain of alphaIISp. This site of interaction was confirmed using site-directed mutagenesis. Two FA proteins that did not contain motifs that bind to SH3 domains, FANCC and FANCF, did not interact with the SH3 domain of alphaIISp. These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.

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