Regulation of Protein Compartmentalization Expands the Diversity of Protein Function

• Published in: Developmental cell Vol. 9; no. 4; pp. 545 - 554
• Main Authors: Shaffer, Kelly L., Sharma, Ajay, Snapp, Erik L., Hegde, Ramanujan S.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01.10.2005; Cell Press
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Calreticulin - genetics; Calreticulin - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Endoplasmic Reticulum - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Humans; Molecular and cellular biology; Molecular Sequence Data; Prolactin - genetics; Prolactin - metabolism; Protein Sorting Signals; Rats; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Transcriptional Activation; Development; Regulation(control); Protein
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2005.09.001

Proteins destined for the secretory pathway are translocated into the endoplasmic reticulum (ER) by signal sequences that vary widely in their functional properties. We have investigated whether differences in signal sequence function have been exploited for cellular benefit. A cytosolic form of the ER chaperone calreticulin was found to arise by an aborted translocation mechanism dependent on its signal sequence and factors in the ER lumen and membrane. A signal sequence that functions independently of these accessory translocation factors selectively eliminated cytosolic calreticulin. In vivo replacement of endogenous calreticulin with a constitutively translocated form influenced glucocorticoid receptor-mediated gene activation without compromising chaperone activity in the ER. Thus, in addition to its well-established ER lumenal functions, calreticulin has an independent role in the cytosol that depends critically on its inefficient compartmentalization. We propose that regulation of protein translocation represents a potentially general mechanism for generating diversity of protein function.