Search

Abstract: The endoplasmic reticulum (ER) is involved in many critical processes, including protein and lipid synthesis and calcium storage. Morphologically, the ER can be divided into two subdomains: a network of interconnected tubules and interspersed sheets. Until recently, how these different compartments form in a continuous membrane system was unclear. Several classes of integral membrane proteins have been identified in the ER; the reticulons and DP1/Yop1p play roles in the generation of ER tubules, and possibly in stabilizing ER sheets, atlastins and Sey1p are dynamin-like GTPases that facilitate tubular network formation by mediating ER membrane fusion, and Climp63, p180, and kinectin are enriched in ER sheets and influence their formation. In this review, we summarize recent advances in our understanding of how these proteins participate in ER shaping. We also discuss possible mechanisms for regulating ER morphology via the cytoskeleton. Lessons learned about sculpting the ER membrane may be applicable to other organelles. [Copyright &y& Elsevier]

Regulated phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) by the endoplasmic reticulum (ER) stress-activated protein kinase PERK modulates protein synthesis and couples the production of ER client proteins with the organelle's capacity to fold and process them. PERK activation by ER stress is known to involve transautophosphorylation, which decorates its unusually long kinase insert loop with multiple phosphoserine and phosphothreonine residues. We report that PERK activation and phosphorylation selectively enhance its affinity for the nonphosphorylated eIF2 complex. This switch correlates with a marked change to the protease sensitivity pattern, which is indicative of a major conformational change in the PERK kinase domain upon activation. Although it is dispensable for catalytic activity, PERK's kinase insert loop is required for substrata binding and for eIF2α phosphorylation in viva. Our findings suggest a novel mechanism for eIF2 recruitment by activated PERK and for unidirectional substrate flow in the phosphorylation reaction. [ABSTRACT FROM AUTHOR]