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ODU CS 791 - Study Notes

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www.sciencemag.org SCIENCE VOL 299 28 FEBRUARY 20031331dase I, assisting this enzyme in the removal ofnoncompliant glycoproteins. Modification ofglycoproteins by ER mannosidase I can belikened to a key and lock in which the Man8glycans form the key shaft and EDEM thelock (see the figure). Questions that remainto be explored include whether, or how,EDEM contributes to the recognition of mis-folded protein structure (the key handle).Regardless of the model, ER mannosidase Iand EDEM are partners in the partitioning ofnewly synthesized glycoproteins between thefolding and disposal pathways.EDEM’s contribution is particularly inter-esting because it binds to the carboxyl-termi-nal tail of calnexin. As Oda et al. demonstrate,the interaction of EDEM with calnexin pro-motes the release of misfolded α1-antitrypsin from calnexin and ac-celerates its degradation (2). Thisobservation raises the possibilitythat calnexin, by interacting withEDEM, actively cooperates in the degradationof defective glycoproteins at least in some celltypes (5). Alternatively, EDEM’s associationwith calnexin might provide newly synthe-sized glycoproteins with a salvage foldingpathway that helps them to acquire their cor-rect conformation. Because mammalianEDEM is part of the unfolded glycoproteinresponse (8), it is fun to speculate that its in-teraction with calnexin might be part of thenormal stress response. Production of EDEMin response to stress could promote cell re-covery by boosting degradation of terminallymisfolded glycoproteins. In support of thisnotion, expression of EDEM has been shownto be necessary for degradation of misfoldedglycoproteins in mammalian cells (11).The new findings have broad implicationsbecause most physiological systems are, attheir core, protein-driven processes. It is cur-rently popular to investigate latent cellular re-sponses to the accumulation of undegradedaberrant proteins during disease pathogenesis.However, it should be noted that degradationis the initial cellular response to protein mis-folding. Whether, and how, either EDEM orcalnexin might contribute to the broad spec-trum of severity observed in certain diseaseswill be an exciting avenue for future study. References1. M. Molinari et al., Science 299, 1397 (2003).2. Y. Oda et al., Science 299, 1394 (2003).3. R. Sifers et al., Mol. Biol. Med. 6, 127 (1989).4. L. Yang et al., Nature Med. 9,3 (2003).5. C. Cabral et al., Tr ends Biochem. Sci. 26, 619 (2001).6. T. Sommer, D. Wolf, FASEB J. 11, 1227 (1997).7. A. Helenius, M. Aebi, Science 291, 2364 (2001).8. N. Hosokawa et al., EMBO Rep. 2, 415 (2001).9. Y.Yoshida et al., Nature 418, 438 (2002).10. C. Jacob et al., EMBO Rep. 2, 423 (2001).11. H. Yoshida et al., Dev. Cell 4, 265 (2003).CREDIT: PRESTON MORRIGHAN/SCIENCEModelcomponentsMolecularequivalentGERADfunctionCellularfactorsLectinGlycan signalrecognition factorEDEMN-linkedoligosaccharidesGlycan signal Man8MisfoldedproteinsMisfoldedproteinsNonglycansignalThe key to quality control. During protein quality control, misfolded glycoproteins areretained in the ER and modified with Man8 glycans formed by the enzyme ER mannosi-dase I. This generates a GERAD signal resulting in transport of the modified aberrant gly-coproteins out of the ER and their degradation by the proteasome (5).The Man8 glycanscan be thought of as the shaft of a key, and the misfolded polypeptides of the aberrantglycoproteins as the key handle. Both the key handle and shaft must be present to initi-ate GERAD. A noncatalytic homolog of ER mannosidase I called EDEM promotes releaseof misfolded glycoproteins from calnexin and boosts their degradation (1, 2). In thismodel, EDEM is the lock.P ERSPECTIVESPrograms for the large-scale DNA se-quencing of animal and plant genomesseem to be perpetually at a crossroads.With completion of the genome sequencingof human, mouse, rat, several fish and small-er model species, the question arises regard-ing which organisms should be analyzednext. Different characteristics (including ex-perimental and economic relevance) makeother creatures attractive candidates forgenome sequencing, but even these criteriagenerate a rather short list. A more com-pelling argument is to distribute sequencingefforts around the tree of life in order tomaximize the discovery of conserved codingsequences (exons) and regulatory elements.On page 1391 of this issue, Rubin and col-leagues (1) present data from their sequenc-ing of select genome regions of multiple pri-mate species closely related to the human.They use these data in a method called “phy-logenetic shadowing” that differs from pre-vious cross-species genomic comparisonsand works very effectively to reveal codingand regulatory regions in the humangenome. Their work argues for prioritizationof the genome sequencing of animals thatare closely related to us.The premise of cross-species genomicdiscovery is that “what is important is con-served.” The basic techniques of cross-species genomic comparison (pioneered longbefore genome-scale DNA sequencing waspossible) and the ability to cross-hybridizeDNA probes among species have been wide-ly used to demonstrate the presence of codingregions in the human genome. The emer-gence of larger amounts of DNA sequenceinformation from distant species has dramat-ically advanced the value of these techniques,because in silico analyses can define con-served regulatory elements in the genomewith high base specificity. Key studies haveshown that gene sequences conserved be-tween human and mouse retained their ca-pacity for tissue-specific expression when re-constructed in appropriate cell types (2).Ansari-Lari et al. (3) found new genes andexons with this approach but also observedlarge numbers of DNA sequence alignmentsbetween mouse and human that were non-coding and apparently nonfunctional. Themouse draft genome sequence (4) revealsthat these alignments sum to a total of about40% of the mouse genome, and their ubiqui-ty has unfortunate practical consequences.Even with the excellent software now avail-able (5), the signal from regulatory regions ofthe genome can be masked by the noise fromsequences that are shared but are of no ap-parent importance. Recent studies from EricGreen’s group show that further calibrationof the phylogenetic distance of pairs ofspecies can improve cross-species compar-isons, but even multiple pairs spaced far apartdo not completely overcome the caveats de-scribed above (6).Rubin and co-workers (1) now offer a


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