Protein Function Prediction ????? ?????? ????????

1
??? ???? ??????
????? ?????? ??????
???? ??? ???? ?"? ???? ?????
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Protein Function Prediction????? ?????? ????????

• James D. Watson, Roman A Laskowski, Janet M
  Thornton
• Predicting protein function from sequence and
  structural data. Current Opinion in Structural
  Biology 15275-284.
• Cambridge, April 2005.

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????????

• ????? ???? ?? ??? ????????Protein Data Bank
  (PDB)
• ????? ???? ?? ??????? "???????" ??????? ?????
  ??????? ???????
• ??????????? ?????? ??????????? ????? ?????
• 1/3 ????????? ????????? "hypothetical"

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??? "??????" (Function) ?? ??????

• ?????? ?? ????? ????? ?????? ????? ?????.
• ?????? ?????? ??????? ????? ????????Gene
  Ontology(GO), Enzyme Commission(EC)
• ?????? ?"? GO ?????? EGFR ?????? ????? ?"?29
  ????????, ????
• calcium-dependent phospholipase A2 activation
• positive regulation of cell migration
• response to stress
• protein binding

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????? ?????? ?????? ??????

• ?? ?? ???? (BLAST, Pfam, InterProScan)?????
  ????? ?????? ??? ????? ?????? ???????? ??????
  (???????? ?????).
• ????? ????????? ?????? ? ORFs ????? ??? ?????
  ????? ???? ?? ??????? ??????.
• ?????? ??????? ???? ??? ???? ???? ?????? ??????
  ????.

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????? ?????? ?????? ??????

• ?? ?? ???????? ????? ?????? (DALI, GRATH, VAST)
• ?????? ??? ???? ????? ????? ??????? ??????
• ????? ???? ???? ?????? ????
• ?? ???? ?????? ????? ????? ???????? ??????.
• ?????? ???? ???? ???? ???????? ???? ?????? ????

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????? ?????? ?????? ??????

• ?? ?? ??????????? ???? ???? ????? ?????(pvSOAR,
  CFG, THEMATICS)
• ?????? ???? ??????? ?????? ??????
• ????? ?????? ???? ?????? ????? ???????

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????? ?????? ?????? ??????

• ?? ???? ???? ????? ??? ?????
• ??????? ???? ?????? ????? ?????????? ????? ??
  ????? ????????

hexokinase
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????? ?????? ?????? ??????

• ?? ?? ?????????? ?????? ??? ??????? (CSA,
  PHUNCTIONER)
• ???? ?????? ??? ?????? ??????? ?? ???????
• ???? ????, ?? ???? ???? ?????? ??????
• ???? ?????? ?????? ?????????? ??????? ????
  False Positives.

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????? ?????? ?????? ??????

• ?? ?? ???? ?????????
• ?????? ????? ?????? ?????? ?????? ?????????
  ?????????
• ????? ????? ?? ???? ?"??????"??????????

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????? ?????? ?????? ?????? - ?????

• ??? ?????? ??????? ?????????? ????? ?????? ?????.
• ?? ??? ?????? ?? ?????? ????? ????? ???? ??????
  ??? ????? (ProFunc, ProKnow)
• ???? ????? - ??????? ?? ?????? ????.
• ????? ?? ??? ?? ??????? ???? ????? ??????

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PHUNCTIONER

• Florencio Pazos Michael J. E. Sternberg
• Automated prediction of protein function and
  detection
• of functional sites from structure.
• PNAS 10114754-14759.
• Imperial College London, October 2004

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- PHUNCTIONER??????

• ???? ???????? ?????? ?????? ??????
• ????? ?????? ??????? ?? ?????? ????????????
• ????? ??????? GO ?????? ??????? ???? ?????
• ????? ???? ?? ?????? ?????? ???????? ????????? GO

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- PHUNCTIONER????? ?????? ????? ??????

• ?????? ?? ??????? ???? ???? ????? ????? FSSP
  (Families of Structurally Similar Proteins)

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- PHUNCTIONER????? ?????? ????? ??????

• ?? ????? ????? ???-??????,?? ????? ??? ????? GO

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- PHUNCTIONER????? ?????? ????? ??????

• ???? ?? ?? ?????
• ??? ???? ???? ???? ????? ??????
• ????? ????? ??????? ?? ?????? ??????
• ????? ????? ???? ?????? ???? ?????"????? ??????
  ?????"

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- PHUNCTIONER????? ?????? ????? ??????

• ??? ????? ????? ?????? ?????? ????? PSSM
  (Position Specific Scoring Matrix)
• ???? ???? Z-score ??? ?????

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PHUNCTIONER ????? ???????

• ?????? ??? SEQID ????? ?????? ??? ???
• ????? ??????? ?????? ?????? ????? ??????
• ????? ?? ??????? ???? ??? (??? ?? ??????)
• ???? ?????? ???? 121 ?????? GO ????? ?????(???
  ????? GO ????? ?????? ??????)
• ?????? ????? ?????? ?-6000 ???????

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PHUNCTIONER ????? ???????
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PHUNCTIONER ????? ???????
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PHUNCTIONER ?????

• ????? ????? ?? ?????? ???????? MTH538
• ??????? ???? ????? ?- Mg2
• ???? PSI-BLAST ???? ???? ?? ???????????? ?????
  ATP
• ?"? PHUNCTIONER
• ???? Mg2 (Z score7.07)
• two-component response reg. activity (Z
  score4.96)
• ????? Ca2(Z score5.18)
• ??? ?????? ?? ????? NTP,Z score0.80 ????
  ????? GTP,Z score1.71 ???? ????? ATP.

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PHUNCTIONER ?????

• ????? ????? ?????? ???? ????? GO
• ???? ???? GTP-binding activity ????? ?????
  ???????? ?? ??? ????? ?????? ?? ?????? Ras

GTP
????? ??????
PHUNCTIONER
SEQUENCESPASE
??? ??????
MTREEDET
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?????
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Switch-of-function????? ?????? ??? ???
???????(?"? ??????? ????????)

• Won Do Heo Tobias Meyer. Switch-of-function
  mutants based on morphology classification of Ras
  superfamily small GTPases. Cell
  113315-328Stanford, California, May 2003.

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?????

• ??? ???????? ???????? ?? ??? ??????? ?????? ??
  ??????? ???? ????
• ????? ?????? ???????? ????? ????????
• ???? ?????? ????? ?????? ?? ???????? ???????
• ??"? ????? ??????? ??????? ??? ???? ?? ???????
  ??????
• ???? ?? ???? ??????? ?????? ?????? ?????

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small GTPases Ras-related

• ?-150 ??????? ?????? ?? ????
• ?????? ??????? ????? ??????? ??????? ???? ???
  ?????? ???
• ??? ????? ???? ???? ???? ?? small-Gs ?????

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??????

• ????? 100 ?????? G ????? ???????
• ?????? ?????? ???? ?? ????? ?????? ?? ??????? ???
  ???? ??????? ???????????
• ???? NIH3T3, ????? ??????? ??? ???
  ????????????? ??????? ??? ?????????? CFP
• 44 ???? ??????? ??????????? ???
• ???? ??? ???? ?? ???????? ?-9 ?????? ??????

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(No Transcript)
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• ???? ??? ????????? ????? ??????? ?? ??? ????
• ??? ???? ???? ????? ?????? ?? ?? ???????? ??????
  ??????, ??????? ???? ?????? ??????

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(No Transcript)
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• ????? CDC42, Rac1 ??????? ????? ?? ??? ??????
  ???? ?????????
• 70 ????? ???? ??? ??????
• ????? 3 ????? ?????? ??? ??????, ???? ????? ?????
  ??????, ?????? ?????? ?????? ????? (??????? ?????)

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???????? ?? ????? ???????? ???????????
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????????? - ???? ?????? ?????? ??? ????
CDC42
Rac1
CDC42h
Rac2
???? ????? ????? ??????? ???????
TC10
Rac3
TCL
RhoG
(filopodia)
(lamellipodia)
????? ?????????? ?????? ?????
???? ??? ????? ???? ?????? ?????
?? ???? ????? 2 ??????
CDC42
???? ??????
???? ?????
????? ??? ???? ????? ?????? ???? ????? ?????
????? ??? ???? ?????? ????? ?????? ????? ????
?????? ?????
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????????? - ???? ?????? ?????? ??? ????
CDC42
Rac1
CDC42h
Rac2
???? ????? ????? ??????? ???????
TC10
Rac3
TCL
RhoG
(filopodia)
(lamellipodia)
????? ?????????? ?????? ?????
???? ??? ????? ???? ?????? ?????
?? ???? ????? 2 ??????
Rac1
???? ?????
???? ??????
35
????? ????
??? ????? ????
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???????? ??????? ???? ??? ???
switch?
?? ???? ????? ?????
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• ????????? ?????
• ????? ??? ??????? ???? ???????? ????
• ???? ?? ???? ???????? ?????? ????
• ???? ?? ???? ?????? ?? ????? ???????
• ???? 54 ??????? ???????? ?????
• ?? ?? ?????? ????? ???????? ??? ????? ??????
  ????? ?????? ???????.

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(No Transcript)
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• ????????? ????? ??? ?????
• Rap2, RalA, R-Ras - ???? ????? (Eyelash)
• H-Ras - ???? ?????? (Polar)

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• ????? ????? ????
• H-Ras ???? ????? ???? ?????
• ?????? ?? ?????? ????? ?? ???? ????? ???????
• ??????? ??????? ??? ?????? ????? ???? ???????
  ?????
• ??? ????? ?? ?? ??????? ??????? ??????

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????? ??????

• ??? ???? ??????? ?-G ?????? ????? ?-9 ?????? ??
  ?? ??????????
• ??? ?????? ?????? ??????? ???? ?????? ?? ??? ????
  ?????? ???????, ??? ??? ???? ?? ???????
• ??? ?????? ?????? ??????? ?????? ???? ?? ???
  ?????? ??????? ?? ???????, ???? ??????? ?? ???
• ???????? ???? ?????? ???? ?????????

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(No Transcript)
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????? ??????

• ??? ????? ??????? ????????? ????? ?????? ?????
  ?????? ?? ?????? ?????? ?? ????????? ???.
• ???????? ?????? ?????? ??????? ????????? ??????
  ????? ???? ?????? ???????? ?????
• ???? ????? ??????? ?? ????????? ?? ?????? ???????
  ?????

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?????? ????

• PHUNCTIONER
• ????? ????? ?????? ?? ??????? ?????
• ???? ?????? ?????? ?????? ?? ?? ????? ???? ??
  ????? ?? ??? ???? ??????? ???????
• ????? ??????? ?????? ?? GO
• ???? ????? ?????? ?? ????? ?????? ???????
  (FSSP,GO) ?? ??? ???? ?????? ????????????

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?????? ????

• Switch-of-function algorithm
• ????? ????? ?????? ????? ???????? ????????
  ??????
• ???? ?????? ?????? ?????? ?? ?? ????? ???? ??
  ????? ?? ??? ???? ??????? ???????
• ????? ??????? ?????? ?? ??????? ???????
• ?? ???? ?????? ???? small GTPases ????? ??
  ??????? ?????

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References

• Watson J.D., Laskowski R. Thornton J.M. (2005).
  Predicting protein function from sequence and
  structural data. Current Opinion in Structural
  Biology 15275-284.
• Pazos F. Sternberg M.J. (2004). Automated
  prediction of protein function and detection of
  functional sites from structure. PNAS
  10114754-14759.
• Heo W. Mayer T. (2003). Switch-of-function
  mutants based on morphology classification of Ras
  superfamily small GTPases. Cell 113315-328.

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???? ???!
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PHUNCTIONER ????? ???????
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PHUNCTIONER - calculations

• ?????? ?????? ????? ?i- ????
• j,k
  ???? ?? ?? ??????
• ??? ??????? ??????
• ????? ?? ????? ?? Zi ??? ?? ????? (Zcut)
• ????? ?? Zi ?????? ?????? ??? ?? (Zocut) ?????
  (?????? ?????)
• ???? ????? ???????? ??? ?????, ???? ?? ????????
  ????? ??????.
• Pik - ??? ?????? ?????
• i ??? ?????? ??????? k

???? ?????
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PHUNCTIONER - calculations

• ????? PSSM ????? n ????? ?? 20 ?. ?????
• (k ?? ?? 20 ?. ?????
• sim ?? ?????? ??? ??. ?-k ??. ???? ?-i)
• (f - ?????? ????? ??. ?-k ????? ?-i.)
• Z score ?? ??????

???? ?????