From proteins t o peptides t o amino acids:
comparative genomics of enzymes involved in
downstream events during cytosolic protein
degradation
Dilip C h a n d u a n d D i p a n k a r N a n d i
Department of Biochemistry, Indian Institute of Science, Bangalore, India
Abstract: Thc role of p r o t c ~ ~
degradation
i
in fixlous hiolop~calfmctions is well knoiin. Proteins targutc6 for destruction are initialli
\veil-studicd.4TP-dependmt
pmtcnses (sg ?6S protsasnlncs. Clp. Lon etc! in bacteria and w h a n otcs Recent studies lhavc
higlillshtrd the role ufcozymus (tricom. rripeptdyl pcpridasr 11. blcom!cin hydrolass. thimst oligopzptidasc. pl-olyl oligoprpiidais.
Ieucinc aminiipeplidasc and 1iuroni)cin sensiti\c aininopeptidase! in thc ATP-independent do~nsti:am psocecsi~igol'pept~ilcsduring
cytusolic protcin drgil~dation.\Ye descnhe putatiw sequence-based ho~niolog~~es
of these c n / ~ m c sin si.preseiiraliie organims from
difizrenl i\inyciunis and alignment of actkc srte reiiduo. Homolopucs olendiipeptidases and some oligoprptidascs !\ cri- ~ i o idcnulied
t
in most represcntatiie orpnlsms, suggesting iprcific~t)during the inltial steps ofdounitream pruccssing. This findinp agrees u ith rhc
k n n n n diffcrcnccs in proteases imolied in rhc iTP-dependent itups of bact~rialand cuknryorlc proism decradutmi. H o u n c i .
am~nopeptidaschomologurs n c i e rcadlly found in most iclirermiati\ s urgamrms, Thris. specific mdoprotmccc peptidasri are ~equil-ud
during tlie p n ~ s ~ r n asteps
l of pnltcin degradation h! d~fferenturganims. Pcptidases ln\ol\?d during rhc lnrtsr steps o r iior\nstwm
priicessing arc rimilq across diffci-cnrhinpdom~.Also. sequence imilril-iry ofpspndas? lhoinologucs fi0!11 diii'erenr organisms ins! lnot
a l n a y corrclals with co~~scrvatloli
of a c r i ~ erltc residue> icy lcucinc ammopsptidasc homologuei in Dr~r.uop/i!/iri i ~ c l i r i ~ o ~ u ~Finally.
~ci!.
fu~rct~m.lly
similar cnzymeb ma) he d~itinct.lacking si.qai.nce lhomolog) i q rricoi-n in T1zi.i-iiiopiosiiiir nctdi~pliiiziiirand tnpeptld>l
pepiidaie TI in niammalsl. The strate?) used in thls srud) ma) he used n) idcnt~ljand btud! thc rolc nf C O I - I ~ C ~ ~ peptldasc
O I ~ ~ I ~ ~
homoiogues in difrerent iirgmisnis. \\i. Ira\? reiicwcd rhe current literature on en/!mei involved l n downsti-em p r o c e s h ? of pmtcins
d u m g cyrosolic protcirl degradation and hiphl~shttheir spccnlissd fiitiiuon, in diffcrzrcnr orpanlsmi. 1 s mhlbiriiin of en71 tner m o l i ed
m gcneral protein t r ~ n i o ~ ae ri l l be detrirncnml lo cell.. a hettsr ilnder\lmding of pspt~dasesand rhcir ipccitic f~nnction~
ma) result in
idmlificat~onofpotent~;rithrrapcutic rai-pets.
K e y o r d s : prulein degradation. cytosol. pept~dawi.peptide procussing, peptiilahr hon101o:ues. pepniiaie auli~i.hit;>
degraded by
Introduction
action during protein.degradation is now an active field of
Cellular proteins are turncd o\ er coiitinuourly and r a p i d ) .
research. .Also. t112 availabl? genome sequences o f different
o y a n i s n i s will caial)se h ~ c t i o i i a lciiauac~erisationand
pro\.ide
a bcrter understanding of different p r o r e a ~ e sin
proteins. R e c e n t a d ~ a n c e sh a l e r e \ c a l e d t h e ~ i t a l
\arious biological iiinctions ( S i ~ u t h a n2001 1.
contribution o f protein ~lcyratiarionin r e g J a t i n g different
Intraccllular proteolysis in e u k a r y o t e s is cornpartc c l l u l a r pi-ocssscs, c: d u r i n s c e l l c ~ c l cp r o g r e s s i o n .
releasing amino acids that are further used to s\-nthcsise
development, transcriptional regulation. strcss response.
menralised into lysosonial and c y t i ~ s o l i cpathways: this
aliligen processing. discasc progression a n d s o o n
rmieii focuses o n the c)tosolic protein degradation
((iottcsman
L\ickncr er a1 1999:
machinery. T h e general m o d c o f i n t r a c e l l i ~ l a rprotcin
degradation. ic rhc h r e a h d o u a o f c d l u l a r prorcins into large
Z\\-ickl et a l 1 0 0 0 ) . .A r?n d c c o d c s a g o . m o s t of r h e
pcptides follm\ed b ? their digestion into smallcr peptider
1 9 9 6 : C o u s c t al 1 9 9 6 : I l e r s h k o a n d
Cicchanovcr 1998: D c M o t e t al l'i'i'l:
kno\\ ledge about 131-oteasss was obtained from ihc stud\- o f
extr;rcellular a n d d i g e s t i \ e protcascs. e g trypsin.
c h > m o t r y p s i n e t c . I I o n e x c r . tlie i d e n t i f i c a t i ii o f
?%
s
inti-acellular protcases peptidases atid their mechanism, o f
Appiied Genomici a n d Proreomicr 2002:1(4) 235-252
O 2002 Open Mind journals L~incedAllr g h t r reserved.
Cairerpondence: Dipankar Nandi. Deparrmenr of Biocheminrry. Indian
Institute &Science. Bangalore-5600l2,lndia;iel +9i 80 394 305 1:fax
1 9 1 80 360 0814; emaii nand@bochem.iisc e r n e t n