Crystal structure of the conserved subdomain of human protein SRP54M at 2.1 angstrom resolution: Evidence for the mechanism of signal peptide binding

Protein SRP54 is an integral part of the mammalian signal recognition parti cle (SRP), a cytosolic ribonucleoprotein complex which associates with ribo somes and serves to recognize, bind, and transport proteins destined for th e membrane or secretion. The methionine-rich M-domain of protein SRP54 (SRP 54M) binds the SRP RNA and the signal peptide as the nascent protein emerge s from the ribosome. A focal point of this critical cellular function is th e detailed understanding of how different hydrophobic signal peptides are r ecognized efficiently and transported specifically, despite considerable va riation in sequence. We have solved the crystal structure of a conserved fu nctional subdomain of the human SRP54 protein (hSRP54m) at 2.1 Angstrom res olution showing a predominantly alpha helical protein with a large fraction of the structure available for binding. RNA binding is predicted to occur in the vicinity of helices 4 to 6. The N-terminal helix extends significant ly from the core of the structure into a large but constricted hydrophobic groove of an adjacent molecule, thus revealing molecular details of possibl e interactions between alpha helical signal peptides and human SRP54. (C) 1 999 Academic Press.