Conformational control through translocational regulation: a new view of secretory and membrane protein folding.
We suggest a new view of secretory and membrane protein folding that emphasizes the role of pathways of biogenesis in generating functional and conformational heterogeneity. In this view, heterogeneity results from action of accessory factors either directly binding specific sequences of the nascent chain, or indirectly, changing the environment in which a particular domain is synthesized. Entrained by signaling pathways, these variables create a combinatorial set of necessary-but-not-sufficient conditions that enhance synthesis and folding of particular alternate, functional, conformational forms. We therefore propose that protein conformation is productively regulated by the cell during translocation across the endoplasmic reticulum (ER), a concept that may account for currently poorly understood aspects of physiological function, natural selection, and disease pathogenesis.
Lingappa
Vishwanath R
VR
Department of Physiology, University of California, San Francisco, CA 94143-0444, USA. vrl@itsa.ucsf.edu
Rutkowski
D Thomas
DT
Hegde
Ramanujan S
RS
Andersen
Olaf S
OS
D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021381:Protein Transport; D015398:Signal Transduction