C V Nicchitta

..Might this abundant chaperone serve an autocrine function in the regulation of CD1d expression?..

..Perspectives on the regulation of and interplay between the peptide binding and chaperone activity of GRP94 and calreticulin are discussed...

..However, recent findings, including new data on the cell biology of peptide generation and trafficking, have called into question the specificity of tumour rejection that is induced by HSPs...

..Recent insights into the pathways for peptide generation now allow this hypothesis to be critically examined, which is the subject of this review...

..A hypothesis identifying the endoplasmic reticulum as a site of mRNA localization and compartmentalized protein synthesis has been suggested...

..Insights into the structural basis of peptide binding to GRP94 have been obtained and the role of the transporter for antigen presentation in defining the GRP94-bound peptide composition has been determined...

..A model describing a potential mode of regulation of the ribosome-membrane junction by the nascent chain is presented...

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..These data identify GRP94 as an antigenic component released upon pathological, but not apoptotic, cell death and provide an assay system for the identification of cellular components of related activity...

..Our model emphasizes a role for the conformation of the large ribosomal subunit in the regulation of membrane affinity and provides a mechanism for translation-coupled ribosome release...

..In this review, key findings on this topic are discussed, and the template-partitioning model, describing a hypothetical mechanism for RNA partitioning in the eukaryotic cell, is proposed...

..These findings identify a role for the ER in global protein synthesis, and they suggest models where compartmentalization of the tRNA acylation/deacylation cycle contributes to the regulation of global protein synthesis rates...

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..In total, these data demonstrate that ribosome and mRNA release from the ER is regulated independent of translation termination and identify the ER as a privileged site for protein synthesis...

..These studies demonstrate that ribosome release from the ER is termination independent and identify new and unexpected roles for the ER compartment in the translational response to induction of the unfolded protein response...

..On the basis of these data, we propose that in situ, ribosomes reside in association with the translocon throughout the cycle of protein synthesis, with membrane release occurring upon translation of proteins lacking topogenic signals...

..Thus, the kinectin cDNA encodes a cytoplasmic-oriented integral membrane protein that binds kinesin and is likely to be a coiled-coil dimer...

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..In this contribution, we briefly review the literature describing the subcellular partitioning patterns of mRNAs and present a detailed methodology for studying this fundamental, yet poorly understood process...

..In addition, macrophages derived from SR-A-/- mice were substantially impaired in gp96 binding and uptake. These data identify new roles for SR-A in the regulation of cellular responses to heat shock proteins...

..Combined, these data indicate that the mRNA localization to the ER can be conferred independent of the signal sequence/SRP pathway and suggest that mRNA localization to the ER may utilize cis-encoded targeting information...

..These data identify a CD91-independent, GRP94 internalization pathway that functions in peptide Ag re-presentation...

..In the following chapter, we provide detailed experimental methods to study protein synthesis initiation on the ER membrane...

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..Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses...

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..This continuation of the beta sheet past the charged domain suggests a structural basis for the association of the N-terminal and middle domains of the full-length chaperone...

..Our results indicate that combined AdsGRP94-based immunotherapy and radiation therapy may be a potentially effective strategy for cancer treatment...

..These results are discussed with respect to current understanding of the contributions of endotoxin and heat shock/chaperone proteins to the stimulation of innate immune responses...

..On the basis of these data, we propose that structural maturation of the client protein substrate, rather than ATP binding or hydrolysis, serves as the primary signal for dissociation of GRP94-client protein complexes...

..These results are discussed with respect to current models for GRP94 function and the role of such co-purifying (poly)peptides in the generation of GRP94-dependent cellular immune responses...

..These results identify a compact, intertwined quaternary conformation of native GRP94 and suggest that intersubunit N+M interactions are integral to the structural biology of Hsp90...

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..By understanding these mechanisms, we hope to identify new targets for therapeutic intervention. ..

..By understanding these mechanisms, we hope to identify new targets for therapeutic intervention. ..

..The investigator proposes a reexamination of current models and assumptions concerning the nature and role of the association of ribosomes and the nascent chain with the ER membrane. ..

..To test whether dimerization is necessary for function, mutations in the assembly domain that block dimerization will be assessed by in vitro studies of peptide binding and in vivo studies of protein assembly and secretion. ..

..By understanding these mechanisms, we hope to identify new targets for therapeutic intervention. ..