2001 Macmillan Magazines Ltd - PDF document

1 2001 Macmillan Magazines Ltd HIGHLIGHTSN
2001 Macmillan Magazines Ltd HIGHLIGHTSNATURE REVIEWS MOLECULAR CELLBIOLOGYVOLUME 2 JULY 2001 In the Golgi,mannose-6-phosphatereceptors (M6PRs) grab newly synthe-sized lysosomal hydrolases by theirsugars to whizz them to their final des-tination,lysosomes.But how do thereceptors themselves know where togo? Two groups now report in Sciencethat the GGA coat adaptors showthem the way.The lysosomal sorting signal wasacidic cluster followed by a dileucinemotifin the cytoplasmic tail oftheM6PR.The AP-1adaptor complexwas the prime suspect for bindingM6PRs and assembling the clathrincoat.It now turns out that it is,in fact,the most recently discovered adaptors„ the GGAs (for Golgi-localized,ear-containing,ARF-binding) „ thatbind to the lysosomal targeting signalsofM6PRs and sort them to lysosomes.GGAs are made offour domains:aVHS domain;a GTP…ARF-bindingdomain (GAT);a hinge that containsbinding sites for clathrin;and a GAEdomain that interacts with -synerginand other regulators ofcoat assembly.The sorting signals ofM6PRs interact-ed specifically with the VHS domainsofGGAs in two-hybrid assays,in pull-down assays and by surface plasmonresonance spectroscopy.Specifically,all three human GGAs,whereas thecation-dependent M6PR preferredGGA1over GGA3,and did not bindGGA2.Immunofluorescence studiesshowed that M6PRs and GGA1 colo-calize in the trans-Golgi network(TGN) and in the cell periphery,andtime-lapse imaging oflive cellsrevealed that GGA1 associates withtubules and vesicles that bud from theTGN.Kornfeld and colleagues show thatthere is a correlation between reducedin vitrobinding ofthe cation-inde-pendent MPR to GGA2 and mis-sort-ing oflysosomal enzymes.Last,Bonifacino and colleagues provideevidence for a functional involvementofGGAs in sorting ofM6PRs,as over-expression ofa dominant-negativeGGA1 construct blocks exit ofthecation-dependent M6PR from theTGN.So GGAs probably function asadaptors between M6PRs,ARF,clathrin and regulators ofcoat assem-bly.But do they recruit receptors intoAP-1…clathrin vesicles or do they buildclathrin-coated vesicles oftheir own?Raluca GagescuReferences and linksORIGINAL RESEARCH PAPERS . Sorting of mannose 6-phosphate receptors(2001) | Zhu, Y. phosphate receptor. yeast that occur in humanin hereditary nonpolyposiscolorectal cancer.These mutationsenhanced survival ofa telomerase-defective strain to a similar extent asdeletion.Inactivatingtelomerase and mismatch repair inanother yeast,Kluyveromyces lactis„ with a pattern oftelomeresequence degeneracy similar to thatfound in human cells „ yieldedsimilar results,indicating that theseobservations may indeed extrapolateto events occurring in mismatchrepair-defective human cells.These experiments raise manyquestions for cancer research.Dohuman telomeres undergo morerecombination in the absence ofmismatch repair? Can mismatchrepair-defective cancer cells get bywithout telomerase? What is therelative importance ofmutationversus telomere maintenance inthese cells? And can we developtherapeutics that reduce mismatchrepair-defective cells back to thestatus ofmere mortals?Cath BrooksbankEditor,Nature Reviews Cancer PROTEIN SORTING IN BRIEF Impairment of the ubiquitin…proteasome system byprotein aggregation. Bence, N. F. et al.ScienceProtein aggregates are a prominent feature ofmanyneurodegenerative diseases.But are these aggregates a cause or aconsequence ofneurotoxicity? The authors show here thatoverexpression ofproteins that are prone to aggregation „ eitherin pericentriolar aggresomes or in amyloid-like fibrils „ inhibitsthe ubiquitin…proteasome system.As proteasomal degradation isessential for cell survival,inhibition ofthis cellular system byprotein aggregation is highly pathogenic. Specific targeting of insect and vertebrate telomereswith pyrrole and imidazole polyamides.The authors report new cell-permeant compounds „ polyamidescontaining two,flexibly linked,hairpin DNA-binding moieties „that specifically target telomeres.Fluorescent analogues ofthesecompounds colocalize with the telomere-binding proteins TRF1and TRF2.These drugs provide a convenient alternative tocurrent cumbersome methods for estimating telomere length.Polyamides ofthis type could become useful tools for telomereresearch,and might even have potential as medicinal agents. Sensitive detection of pathological prion protein bycyclic amplification of protein misfolding.Saborio, G. P. The infectious prion protein,PrP,is thought to work bycatalysing the conversion ofthe cellular glycoprotein PrPinto itsinfectious form.So far,although there is evidence that prions arepresent in body fluids,it has proved difficult to detect theinfectious prion in patients before death.Here,Saborio et al.ultrasound to free prions from plaques in vitro,which speeds upthe conversion cycle.This might allow diagnosis ofthe presence ofinfectious prions in the bloodstream. G-protein signalling through tubby proteins.Loss oftubby function leads to obesity.In this study,tubby isshown to act downstream ofG-protein-coupled-receptors topotentially regulate gene transcription.Tubby localizes to theplasma membrane by interacting,through its carboxy-terminaltubbydomain,with phosphatidylinositol-4,5-bisphosphate(PtdIns(4,5)P).However,activation ofG-coupled receptorsleads to PtdIns(4,5)Phydrolysis „ probably by increasingactivity.Tubby then translocates to the nucleus,where it might influence genes involved in energy homeostasis. SIGNALTRANSDUCTION PRIONS TECHNIQUE PROTEIN DEGRADATION