Enhanced Level of Site-Specific Proteolysis of GAP-43 Protein during Early Stages of Brain Development

M. I. Mosevitsky^1*, E. S. Konovalova¹, N. K. Bichevaya², and B. I. Klementiev²

¹Petersburg Institute of Nuclear Physics, Russian Academy of Sciences, Gatchina, Leningrad Region, 188350 Russia; fax: (812) 713-2303; E-mail: mm5768@mm5768.spb.edu

²Institute of Experimental Medicine, Russian Academy of Medical Sciences, ul. Akademika Pavlova 12, St. Petersburg, 197376 Russia; fax: (812) 234-8994; E-mail: klement@BK2719.spb.edu

^* To whom correspondence should be addressed.

Received October 25, 1999; Revision received April 7, 2000

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GAP-43 protein of nerve terminals (B-50, F1, F57, pp46, neuromodulin) is thought to be one of key proteins involved in the control of outgrowth of neurites, release of neuromediators, synapse plasticity, etc. GAP-43 is usually considered as a whole protein. Along with the intact protein, nerve cells also contain two large native fragments of GAP-43 deprived of four or of about forty N-terminal amino acid residues (GAP-43-2 and GAP-43-3, respectively). The full-length GAP-43 is predominant in the mature brain. However, the ratio of the full-length protein and its fragments can vary under different physiological conditions. Changes in the GAP-43 proteins (the full-length protein and its fragments) were studied during embryonal and postnatal development of rat brain. The GAP-43 proteins were found to be expressed not later than on the 12-13th day of embryogenesis. Then their contents increased, and, until the 10th day after birth, GAP-43-3 dominated rather than the full-length protein. It is suggested that during this period the activity of a specific protease, which cleaves the N-terminal peptide of about 40 residues from the full-length GAP-43 molecule, is increased. The cleavage occurs in the region responsible for the interaction of GAP-43 with calmodulin. In the full-length molecule, this region is responsible also for the recognition of Ser41 residue by protein kinase C during phosphorylation. Another functionally important region that determines, in particular, the attachment of GAP-43 to the plasma membrane is cleaved from the main part of the molecule together with the N-terminal peptide. Thus, the specific fragmentation of GAP-43 that depends on developmental stage should be considered as a controlled structural rearrangement fundamentally affecting the functions of this protein.

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KEY WORDS: GAP-43 protein of nerve terminals, neuroontogenesis, site-specific proteolysis

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