A genetic approach to detect muscle protein interactions in vivo

An organism is required to identify biologically relevant protein interacti ons. We propose Drosophila and its indirect flight muscles as a suitable ex perimental system for genetic screenings for muscle protein interactions. T he first attempt focused on troponin I (TnI) in view of the key role in thi n filament regulation that this protein performs. Suppressors of a defined Tn I allele have been isolated as mutations in the heavy chain of myosin (M hC). This unsuspected functional interaction between TnI and MhC serves to illustrate one of the benefits of the approach. Four of the suppressors ide ntified to date reside in the MhC head, around the actin-binding site and n ear the lips of the pocket where ATP is hydrolyzed. Two other suppressors c orrespond to a second site mutation in TnI and a mutation in the conserved region of Tropomyosin II (TmII), respectively. All the identified suppresso rs are mutations in constituents of the sarcomere, and most of them are str ucturally similar to human mutations causing familial hypertrophic cardiomy opathy (FHC). At least seven sarcomere proteins can lead to FHC and, conseq uently, the disease is heterogeneous and difficult to diagnose. In addition , putative natural suppressors may help obscure the origin of FHC. The gene tic procedure, used here for muscle proteins, could help diagnose FHC and o ther myopathies, and extend to proteins of clinical interest in other tissu es, including the nervous and circulator systems. (Trends Cardiovasc Med 20 00;10:293-298). (C) 2001, Elsevier Science Inc.