Proteases in Health and Disease PDF
Preview Proteases in Health and Disease
AcademicPressisanimprintofElsevier 32JamestownRoad, London,NW17BY,UK Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands 30CorporateDrive,Suite400,Burlington,MA01803,USA 525BStreet,Suite1900,SanDiego,CA92101-4495,USA (cid:2) Thisbookisprintedonacid-freepaper. Copyright(cid:1)2011,ElsevierInc.AllRightsReserved Nopartofthispublicationmaybereproduced,storedinaretrievalsystemortransmittedinany formorbyanymeanselectronic,mechanical,photocopying,recordingorotherwisewithoutthe priorwrittenpermissionofthePublisher PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights DepartmentinOxford,UK:phone(+44)(0)1865843830;fax(+44)(0)1865853333; email:permissions@elsevier.com.Alternativelyyoucansubmityourrequestonlineby visitingtheElsevierwebsiteathttp://elsevier.com/locate/permissions,andselecting ObtainingpermissiontouseElseviermaterial Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersonsor propertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseoroperation ofanymethods,products,instructionsorideascontainedinthematerialherein.Becauseofrapid advancesinthemedicalsciences,inparticular,independentverificationofdiagnosesanddrug dosagesshouldbemade LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN:978-0-12-385504-6 ISSN:1877-1173 ForinformationonallAcademicPresspublications visitourwebsiteatelsevierdirect.com PrintedandBoundintheUSA 11 12 13 14 10 9 8 7 6 5 4 3 2 1 Contributors Numbersinparenthesesindicatethepagesonwhichtheauthors’contributionsbegin. NsikanAkpan,DepartmentofPathology&CellBiology;andDepartmentof Neurology,TaubCenterfortheStudyofAlzheimer’sDiseaseandtheAging Brain,ColumbiaUniversityCollegeofPhysiciansandSurgeons,NewYork, USA(265) ToniM.Antalis,CenterforVascularandInflammatoryDiseases,Universityof MarylandSchoolofMedicine,Baltimore,Maryland,USA(1) Hans Brandstetter, Department of Molecular Biology, University of Salzburg,Salzburg,Austria(51) Thomas H. Bugge, Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research,NationalInstitutesofHealth,Bethesda,Maryland,USA(1) Raimondo De Cristofaro, Institute of Internal Medicine and Geriatrics, Physiopathology of Haemostasis Research Center, Catholic University SchoolofMedicine,Rome,Italy(105) Enrico Di Cera, Department of Biochemistry and Molecular Biology, Saint LouisUniversitySchoolofMedicine,St.Louis,Missouri,USA(145) Peter G.W. Gettins, The Center for Structural Biology; and Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago,Illinois,USA(185) Jeff W. Hill, Department of Neurology, University of New Mexico Health SciencesCenter,Albuquerque,NewMexico,USA(241) Ying Y. Jean, Department of Pathology & Cell Biology; and Department of Neurology,TaubCenterfortheStudyofAlzheimer’sDiseaseandtheAging Brain,ColumbiaUniversityCollegeofPhysiciansandSurgeons,NewYork, USA(265) StefanoLancellotti,InstituteofInternalMedicineandGeriatrics,Physiopa- thology of Haemostasis Research Center, Catholic University School of Medicine,Rome,Italy(105) Steven T. Olson, Center for Molecular Biology of Oral Diseases; and The Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois,USA(185) Gary A. Rosenberg, Department of Neurology, University of New Mexico HealthSciencesCenter,Albuquerque,NewMexico,USA(241) ix x contributors CarolM.Troy,DepartmentofPathology&CellBiology;andDepartmentof Neurology,TaubCenterfortheStudyofAlzheimer’sDiseaseandtheAging Brain,Columbia UniversityCollegeofPhysiciansandSurgeons,NewYork, USA(265) Qingyu Wu, Molecular Cardiology/Nephrology & Hypertension, Lerner Re- searchInstitute/NB20,ClevelandClinic,Cleveland,Ohio,USA(1) YiYang,DepartmentofNeurology,UniversityofNewMexicoHealthSciences Center,Albuquerque,NewMexico,USA(241) Thomas Zo¨gg, Department of Molecular Biology, University of Salzburg, Salzburg,Austria(51) Preface Proteases act as positive or negative effectors of numerous biological processes, either as nonspecific catalysts of protein degradation or highly selective agents controlling physiological events. Many biological pathways involving protease activity have been characterized, and a wealth of informa- tionisavailable.Fiveclassesofproteolyticenzymesarerecognizedonthebasis oftheircatalyticmechanism:aspartic,cysteine,metallo-,threonine,andserine peptidases. With the advent of whole genome sequencing, this classification system has expanded by the necessity to encompass the diverse catalytic repertoire found in nature. Much work remains to define the diversity of proteolyticeventsinbiologicalsystemsandtheirspatialandtemporaldistribu- tioninhealthanddisease.Thisvolumecontainssevenchapterscontributedby leaders in their field and provides illustrative examples of the key role of proteasesinbiologicalprocesses,andhowproteolyticfunctionandregulation can be harnessed to define new strategies of therapeutic intervention. The readerwillfindthesechaptersbothstimulatingandinformative. In Chapter 1, Antalis, Bugge, and Wu discuss the exciting group of membrane-anchored serine proteases that have emerged as crucial contribu- torstoprocessesrelatedtodevelopmentandmaintenanceofhomeostasis. In Chapter2, Zogg and Brandstetter review the assembly of multiprotein complexesinbloodcoagulation,withemphasisontheirstructuralorganization, modesofaction,andregulation,andoutlinetherapeuticopportunitiesforthe treatmentofhemophiliaandthrombosis. In Chapter 3, Lancellotti and De Cristofaro detail the structural and functional properties of ADAMTS13, a disintegrin and metalloprotease involved in the pathogenesis of thrombotic microangiopathies via processing ofmatrixcomponents. In Chapter 4, Di Cera reviews the structure, function, and regulation of thrombin and how this knowledge has led to the rational engineering of thrombinvariantswithintriguinganticoagulantandantithromboticproperties, bothinvitroandinvivo. In Chapter 5, Olson and Gettins offer an extensive review of protein inhibitors of the serpin superfamily, detailing their structural and kinetic properties and how this knowledge may lead to engineering variants with desiredspecificitytowardproteasetargetsfortherapeuticapplications. xi xii preface In Chapter 6, Yang, Hill, and Rosenberg discuss the multiple roles of metalloproteases in neurological disorders, especially their ability to open the blood-brainbarrieranddegradetheextracellularmatrixaroundbloodvessels, andoutlinetheadvantagesofmorespecificinhibitors. InChapter7,Troy,Akpan,andJeandealwiththeregulationofcaspasesin thenervoussystemanddiscusstheirfunctioninthecontextofneurodegenera- tivediseaseslikeAlzheimer’sandcerebralischemia. I thank all the authors for their excellent contributions and their efforts to submit outstanding chapters by the stringent deadlines agreed with the publisher.ExperteditorialassistancefromTraceyBaird,SeniorAdministrative Assistant,isgratefullyacknowledgedandwaskeytothetimelyexecutionofthis project. September1,2010 ENRICODICERA St.Louis,Missouri Membrane-Anchored Serine Proteases in Health and Disease ToniM.Antalis,*ThomasH. Bugge,{andQingyuWuz *CenterforVascularandInflammatory Diseases,UniversityofMarylandSchoolof Medicine,Baltimore,Maryland,USA { ProteasesandTissueRemodelingSection, OralandPharyngealCancerBranch, NationalInstituteofDentaland CraniofacialResearch,NationalInstitutesof Health,Bethesda,Maryland,USA z MolecularCardiology/Nephrology& Hypertension,LernerResearchInstitute/ NB20,ClevelandClinic,Cleveland,Ohio, USA I.Introduction.................................................................................. 2 II.StructuralFeatures......................................................................... 4 A. CatalyticDomains...................................................................... 5 B. Extracellular‘‘Stem’’Regions........................................................ 6 C. Membrane-AnchoringDomains.................................................... 6 III.RegulationbyEndogenousInhibitors.................................................. 7 IV.TheTypeITransmembraneSerineProtease......................................... 7 A. Tryptaseg1.............................................................................. 7 V.TheTypeIITransmembraneSerineProteases....................................... 8 A. HEPSIN/TMPRSSSubfamily....................................................... 8 B. MatriptaseSubfamily.................................................................. 17 C. CorinSubfamily........................................................................ 24 D. HAT/DESCSubfamily................................................................ 28 VI.TheGPI-AnchoredSerineProteases................................................... 30 A. Prostasin.................................................................................. 30 B. Testisin.................................................................................... 32 VII.Perspectives.................................................................................. 33 References.................................................................................... 34 Serine proteases of the trypsin-likefamily have long been recognized to be criticaleffectorsofbiologicalprocessesasdiverseasdigestion,bloodcoagula- tion,fibrinolysis,andimmunity.Inrecentyears,asubgroupoftheseenzymes hasbeenidentifiedthatareanchoreddirectlytoplasmamembranes,eitherby acarboxy-terminaltransmembranedomain(TypeI),anamino-terminaltrans- membranedomainwithacytoplasmicextension(TypeIIorTTSP),orthrough ProgressinMolecularBiology Copyright2011,ElsevierInc. andTranslationalScience,Vol.99 1 Allrightsreserved. DOI:10.1016/S1877-1173(11)99001-2 1877-1173/11$35.00 2 ANTALIS ET AL. aglycosylphosphatidylinositol(GPI)linkage.Recentbiochemical,cellular,and in vivo analyses have now established that membrane-anchored serine pro- teasesarekeypericellularcontributorstoprocessesvitalfordevelopmentand themaintenanceofhomeostasis. Thischapterreviewsourcurrentknowledge ofthebiologicalandphysiologicalfunctionsoftheseproteases,theirmolecular substrates,andtheircontributionstodisease. I. Introduction Proteolytic enzymes comprise over 2% of the known proteome, and their participation in many essential biological processes is well established. The serine proteases constitute one of the largest families of proteolytic enzymes and are well recognized for their pivotal roles in physiological processes as diverse as development, digestion, coagulation, inflammation, and immunity. Theseenzymesshareacommoncatalyticmechanismforselectivecleavageof specificsubstratesandarefrequentlyinvolvedinconsecutiveproteolyticreac- tions or protease cascades, where one protease precursor or zymogen is the substrateforanactiveprotease.Thissharedmechanismconferstheadvantage that a single signal may be specifically and irreversibly amplified every time a downstreamzymogenisactivated,providingthecapacityforunleashingaburst ofproteolyticpotential. Most of the well-characterized members of the S1 family of serine pro- teases are either secreted enzymes or exocytosed from secretory vesicles into the extracellular environment. Trypsin and chymotrypsin, the main intestinal digestive enzymes, are prototype members of the S1 family. Over the past 10 years,astructurallydistinctgroupofS1serineproteases,termedbroadlyasthe membrane-anchored serine proteases, has emerged that are synthesized with amino-orcarboxy-terminalextensionsthatservetoanchortheirserineprote- asecatalyticdomainsdirectlyattheplasmamembrane1,2(Fig.1). The largest group of membrane-anchored serine proteases is the Type II transmembrane serine proteases or TTSPs.1 These proteases are synthesized withanamino-terminalsignalanchorthatisnotremovedduringsynthesis,but serves as a transmembrane domain that positions the protease in the plasma membrane with a cytoplasmic amino-terminal domain of variable length (20– 160 amino acids) and the catalytic serine protease domain at the carboxy- terminus.1 These serine proteases are synthesized as single-chain precursors orzymogens;activationproducesatwo-chainformwiththechainslinkedbya disulfide bridge, so that the active enzyme remains membrane bound. Nine- teen human TTSPs have been identified and may be categorized into four subfamilies:Hepsin/TMPRSS,Matriptase,HAT/DESC,andCorin3,4(Fig.1). Type l transmembrane Intracellular Extracellular 265 38 Tryptase gamma 1 CO2H S D H NH2 S S Type ll transmembrane Hepsin/TMPRSS subfamily 21 4352 172183223225334342 504524 634642678 769784 1014 Enteropeptidase H2N H D S CO2H 21 4354 151 162 400 S S Hepsin H2N H D S CO2H S S 83 106112149150 242255 484 TMPRSS2 H2N H D S CO2H S S 49 71107108 205216 444 TMPRSS3 H2N H D S CO2H S S 31 5494104 194205 429 TMPRSS4 H2N H D S CO2H S S 48 70 112 207 217 448 Spinesin/TMPRSS5 H2N H D S CO2H S S 161 183 198222223 310320 549 MSPL H2N H D S CO2H S S Matriptase subfamily 55 7785 193 214 334340 447452487524566604614 849 Matriptase H2N H D S CO2H S S Matriptase-2 H2N 44 6675 190 213 321326 443448481521558569H D S797CO2H S S 77 99101 226247 360365 478 483524558596605 835 Matriptase-3 H2N H D S CO2H 28 50153191202 431503 S 731826 S 1053 Polyserase-1 H2N H D S H D S H D S CO2H S S S S S S Corin subfamily Corin H2N 46 68138248268305341378417452454575579617655690 786801H D S1130CO2H HAT/DESC subfamily S S HAT H2N21 44 153 186H D S417CO2H DESC1 H2N21 4366 176 S211H DS S442CO2H TMPRSS11A/HATL1 H2N21 4346 158 S189H DS S415CO2H 30 5257 167208S S 439 HATL4/TMPRSS11F H2N H D S CO2H HATL5/TMPRSS11B H2N19 4143 152S184H DS S410CO2H S S GPI anchored 281 45 Prostasin CO2H 281S SD H42S NH2 Intracellular Testisin CO2H S SD HS NH2 Extracellular Protease domain H D S TM LDLRA domain CUB domain Frizzled domain Activation domain GPI anchor MAM domain SEA domain SR domain FIG.1. Domainstructuresofthehumanmembrane-anchoredserineproteases.Structuresare grouped according to similarity in domain structure to each other. Consensus domains are as indicatedatthebottomofthefigure.Thelocationofeachproteindomain(aminoacidnumbering) isindicatedabovethedomain.Aminoandcarboxyterminiareasindicated.Proteasedomain:serine protease domain; activation domain: pro-domain; TM: transmembrane domain; GPI anchor: glycosylphosphatidylinositol linkage domain; LDLRA: LDL receptor class A domain; MAM: meprin,A5antigen,andreceptorproteinphosphatasemdomain;CUB:Cls/Clr,urchinembryonic growthfactorandbonemorphogeneticprotein-1;SEA:seaurchinspermprotein,enteropeptidase, agrindomain;Fz:frizzleddomain;SR:GroupAscavengerreceptordomain.ModifiedfromRef.2. 4 ANTALIS ET AL. Mammalian orthologs, as well as different isoforms between humans and rodents,existformanyifnotalloftheTTSPs.4–6Therealsoexisttwononmam- malianTTSPs,Drosophilastubble-stubbloid(st-sb)7andcorin.8 IncontrasttotheTTSPs,additionalmembrane-anchoredserineproteases of the S1 family each possess an amino-terminal signal peptide and enter the secretory pathway. These enzymes are also synthesized as zymogens, with an amino-terminal extension that acts as a pro-peptide, requiring proteolytic cleavage to generate the active enzyme. The Type I transmembrane serine protease, tryptase g1, is the only humanmembrane-anchoredserine protease synthesized with a carboxy-terminal hydrophobic extension that serves as a transmembrane domain.9,10 The carboxy-terminal extensions of prostasin and testisin are modified posttranscriptionally with a glycosylphosphatidylinositol (GPI)linkagethatanchorstheseproteasesintheplasmamembrane.11–15 The membrane-anchored serine proteases are proving to be key compo- nents of the cell machinery for activation of precursor molecules in the peri- cellularmicroenvironment,withseveralplayingvitalrolesduringdevelopment and themaintenanceofhomeostasis. Thereisalso growing evidencefortheir participation in the pathogenesis of inflammatory and neoplastic diseases. Endogenous protein substrates targeted by membrane-anchored serine pro- teasesincludepeptidehormones,growthanddifferentiationfactors,receptors, enzymes, adhesion molecules, and viral coat proteins.16 A number of insights intoourunderstandingoftheuniquephysiologicalfunctionsofthemembrane- anchored serine proteases and their involvement in human pathology have comefromacombinationofbiochemicalanalyses,animalmodels,andhuman patient studies. However, our current understanding of the impact of the membrane-anchored serine proteases on many biological, physiological, and pathologicalprocessesisfarfromcomplete.Thischapterprovidesahistorical perspective on the discovery of these enzymes, current knowledge of their activitiesandtheirregulation,andthefunctionalconsequencesoftheactivities of these proteases in mammalian physiology and disease. For the interested reader,severalotherreviewshavefocusedondifferentaspectsoftheirnomen- clature,classificationsintosubgroups,genestructureandchromosomallocali- zation,tissue-andcell-specificdistribution,andbiochemicalproperties.1–4,16,17 II. Structural Features Allofthemembrane-anchoredserineproteaseshavemembrane-anchoring domains and structurally conserved serine protease catalytic domains. The TTSPs have additional extracellular stem regions that separate the catalytic domains from their transmembranedomains. The extracellular regions of the membrane-anchored serine proteases are believed to be essential to the biologicalandphysiologicalfunctionsascribedtotheseenzymes. MEMBRANE-ANCHOREDSERINEPROTEASES 5 A. Catalytic Domains The zymogenformsof themembrane-anchored serineproteases are acti- vatedbyproteolyticcleavagefollowinganarginineorlysineaminoacidpresent inahighlyconservedactivationmotifseparatingthepro-andcatalyticdomains. Thecatalyticmechanismofthemembraneserineproteasesinvolvesacatalytic triad of three amino acids, serine (nucleophile), aspartate (electrophile), and histidine (base), present in highly conserved sequence motifs. While the geo- metric orientations of these amino acid residues are similar, the protein folds are variable, which contribute to their selective substrate specificities. The catalyticreaction followsatwo-stepmechanismforhydrolysisofsubstratesin whichacovalentlylinkedenzyme-peptideintermediateisformed,withtheloss of a peptide fragment.18 This acylation step is followed by a deacylation step whichoccursbyanucleophilicattackontheintermediatebywater,resultingin hydrolysisofthepeptide. Some insights into the structural features that contribute to the unique catalyticandsubstratespecificitiesofthemembrane-anchoredserineproteases havebeenobtainedthroughcomparativeanalysesofaminoacidsequences1,2,19 combined with tertiary structural analyses.20–26 Consistent with the family of S1serineproteases,eachcatalyticdomainpossessestwoadjacent,six-stranded b-barrel domains that are connected by three trans-domain segments. The catalytic triad amino acids are located along the junction between the two barrels, with the active site cleft running perpendicular to this junction.27 The size, shape, and charge distribution within the formed binding pocket of theactiveenzymearedeterminantsofsubstratespecificity.Thesepocketsare defined by differing substrate-binding subsites (e.g., S –S 0) and loop regions 4 2 thatsurroundtheactivesitecleft.23 Thespecificityforcleavageofsubstrateswiththepositivelychargedamino acid residues, lysine or arginine, in the P position (the position directly 1 preceding the cleaved peptide bond) is conferred by the presence of a con- served aspartate residue at the bottom of the binding pocket of all of the activated enzymes.2 The rate of cleavage is influenced by the amino acid residues surrounding the P residue, numbered P to P , counting outward 1 1 n from the amino-terminal side of the peptide bond that is cleaved during hydrolysis, and numbered P 0 through P 0 from the carboxy-terminal side.28 1 n In recent years, recombinant catalytic domains of several of the membrane- anchored serine proteases have been produced in various laboratories and peptidescreeningassaysappliedtoquantitativelyidentifycleavagepreferences fortheP andP 0 aminoacids,andsurroundingaminoacidpositions.29–35 1 1 SeveralofthebiochemicallypurifiedTTSPsrapidlyundergoautocatalytic activation in vitro (matriptase29,36 matriptase-2,37 hepsin,38 TMPRSS2,39 TMPRSS3,40 TMPRSS4,41 HAT-like 3/TMPRSS11C42). Thus, mutation of
The list of books you might like
