Protein elongation arrest

The signal recognition particle (SRP) is a cytosolic ribonucleoprotein complex which binds to signal sequences of nascent membrane and secretory proteins emerging from ribosomes. The SRP consists of a 7S RNA and at least six polypeptide subunits (relative molecular masses 9, 14, 19, 54, 68, and 72 kD). It induces an elongation arrest until the nascent chain/ ribosome/SRP complex reaches the translocon at the endoplasmic reticulum (ER) membrane. 

Walter, P., and Blobel, G. (1981a). Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specific arrest of chain elongation that is released by microsomal membranes. J. Cell Biol. 91, 557-561. 

Vectorial translation [31,32]. Polypeptides are made on membrane-bound polysomes. Many of these proteins are synthesized with a 16-30 amino acid extension at the NH2-terminus. This signal sequence is hydrophobic in nature. Protein synthesis and translocation, into or across the membrane, are obligatorily linked. Therefore, the transmembrane movement is co-translational and it is coupled to the elongation of the polypeptide chain. Consequently, the completed polypeptide chain is never present in the compartment where it is synthesized. The polypeptides that do not yet cross the membrane are shorter than the mature protein. Addition of inhibitors of protein synthesis immediately arrest movement of the polypeptide across the membrane. 

In addition to TFIIS, several other proteins influence Pol II elongation, pausing, and arrest, and some of these factors are involved in disease (Conaway and Conaway, 1999 Shilatifard, 1998a, 1998b). Deregulation of Pol II elongation can lead to certain types of cancer (Groudine and Krumm, 1995). 

In a pioneering paper on the cytochalasan molecular mode of action, Spudich and Lin discovered a decrease in viscosity of actomyosin from rabbit muscle - the active protein complex of actin and myosin - when treated with cytochalasin B (1088) in micromolar concentrations. Actin was identified as direct binding partner of cytochalasin B (1088), thus the first proof on the target of this compound was provided (705). Further studies by several groups revealed that cytochalasins B (1088) and D (1091) inhibit, but not completely arrest, actin filament elongation (708, 709). A plausible mechanism was proposed by Goddette and Frieden (710). 

Kroll SL, Paulding WR, SchneU PO, Barton MC, Conaway JW, Conaway RC, Czyzyk-Krzeska MR Von Hippel-Lindau protein induces hypoxia-regulated arrest of tyrosine hydroxylase transcript elongation in pheochromocytoma cells. J Biol Chem 1999 274 30109-30114. 

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