Subunit Interactions of the Nerve and Epidermal Growth Factor Complexes: Protection of the Biological Subunit from Proteolytic Modification

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Abstract
The nerve growth factor dimer (.beta.NGF) can undergo two proteolytic modifications, one near the amino terminus where a unique histidine/methionine bond is cleaved and the other at the carboxy terminus releasing the terminal arginine residue. The modification near the amino terminus, releasing the first eight amino acids as an octapeptide, occurs as the result of the action of a specific endopeptidase present in the submaxillary gland. This same enzyme was found to be present in high concentration in epinephrine-stimulated saliva (20 mM) and was isolated from this source. The subunit interactions in 7S NGF were considered by assessing the protection afforded by each subunit, individually and in combination, against these two proteolytic modifications. Similar experiments were attempted with high molecular weight epidermal growth factor (HMW-EGF), an analogous growth factor complex that can experience a single modification, the release of arginine by carboxypeptidase B from the carboxy terminus of its biological subunit, low molecular weight EGF (LMW-EGF). The amino terminal octapeptide of .beta.NGF is protected by both the .alpha. and .gamma. subunits of 7S NGF and its loss has no effect on 7S NGF complex stabilization by zinc. The carboxy terminal arginine is protected only by the .gamma. subunit. A scheme depicting the subunit interactions in 7S NGF is presented.