| General information | | DisProt: | DP00748 | | Name: | Adapter molecule crk | | Synonym(s): | CRK_HUMAN
Proto-oncogene c-Crk
p38
CrkII or CRKII
Crk-II
[Crk-I is Isoform 2, see DP00748_A002]
| | First appeared in release: | Release 6.02 (05/24/2013) | | UniProt: | P46108 | | UniGene: | Hs.461896 | | SwissProt: | CRK_HUMAN | | TrEMBL: | | | NCBI (GI): | | | Source organism: | Homo sapiens (Human) | | Sequence length: | 304 | | Percent disordered: | 51% | | Homologues: | |
| Native sequence |
10 20 30 40 50 60
| | | | | |
MAGNFDSEER SSWYWGRLSR QEAVALLQGQ RHGVFLVRDS STSPGDYVLS VSENSRVSHY - 60
IINSSGPRPP VPPSPAQPPP GVSPSRLRIG DQEFDSLPAL LEFYKIHYLD TTTLIEPVSR - 120
SRQGSGVILR QEEAEYVRAL FDFNGNDEED LPFKKGDILR IRDKPEEQWW NAEDSEGKRG - 180
MIPVPYVEKY RPASASVSAL IGGNQEGSHP QPLGGPEPGP YAQPSVNTPL PNLQNGPIYA - 240
RVIQKRVPNA YDKTALALEV GELVKVTKIN VSGQWEGECN GKRGHFPFTH VRLLDQQNPD - 300
EDFS
|
| Functional narrative |
Adapter molecule crk is a proto-oncogene existing in two isoforms, Crk-II and Crk-I. Crk-II is the UniProt canonical sequence [DP00748], comprising aa 1-304. Crk-I is UniProt alternatively-spliced product 2 [DP00748_A002], comprising aa 1-204 of canonical sequence and including a variation at N204R.
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"CRK regulates transcription and cytoskeletal reorganization during cell growth, motility, proliferation, adhesion, differentiation and apoptosis by acting as an adaptor to link tyrosine kinases and small G proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK." (Kobashigawa et al, 2007, and references therein)
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From UniProt: The Crk-I and Crk-II forms differ in their biological activities. Crk-II has less transforming activity than Crk-I. Crk-II mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4. May regulate the EFNA5-EPHA3 signaling.
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|
| Map of ordered and disordered regions |
Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.
|
| Region 1 | | Type: | Disordered | | Name: | N-terminal | | Location: | 1 - 9 | | Length: | 9 | | Region sequence: |
MAGNFDSEE | | Modification type: | Native
| | PDB: | 2EYZ:A, 2DVJ:A, 2EYV:A | | Structural/functional type: | Relationship to function unknown
| | Functional classes: | Modification site
| | Functional subclasses: | Acetylation
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; EDTA 1 mM; DTT 2 mM; NaCl 150 mM; 90% H2O/10% D2O; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 2 | | Type: | Ordered | | Name: | SH2-SH2 domain | | Location: | 10 - 120 | | Length: | 111 | | Region sequence: |
RSSWYWGRLSRQEAVALLQGQRHGVFLVRDSSTSPGDYVLSVSENSRVSHYIINSSGPRP
PVPPSPAQPPPGVSPSRLRIGDQEFDSLPALLEFYKIHYLDTTTLIEPVSR | | Modification type: | Native
| | PDB: | 2EYZ:A, 2DVJ:A, 2EYV:A | | Structural/functional type: | Function arises from the ordered state
| | Functional classes: | Modification site
Molecular recognition effectors
| | Functional subclasses: | Autoregulatory
Protein-protein binding
Intraprotein interaction
Phosphorylation
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; DTT 2 mM; EDTA 1 mM; NaCl 150 mM; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 3 | | Type: | Disordered | | Name: | linker | | Location: | 121 - 133 | | Length: | 13 | | Region sequence: |
SRQGSGVILRQEE | | Modification type: | Native
| | PDB: | 2EYZ:A, 2DVJ:A, 2EYV:A, 2EYW:A | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | Entropic chain
Molecular assembly
| | Functional subclasses: | Intraprotein interaction
Flexible linkers/spacers
Autoregulatory
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; EDTA 1 mM; DTT 2 mM; NaCl 150 mM; 90% H2O/10% D2O; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 4 | | Type: | Ordered | | Name: | nSH3 domain | | Location: | 134 - 191 | | Length: | 58 | | Region sequence: |
AEYVRALFDFNGNDEEDLPFKKGDILRIRDKPEEQWWNAEDSEGKRGMIPVPYVEKYR | | Modification type: | Native
| | PDB: | 2EYZ:A, 2DVJ:A, 2EYW:A | | Structural/functional type: | Function arises from the ordered state
| | Functional classes: | Modification site
Molecular recognition effectors
| | Functional subclasses: | Intraprotein interaction
Phosphorylation
Protein-protein binding
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; DTT 2 mM; EDTA 1 mM; NaCl 150 mM; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 5 | | Type: | Disordered | | Name: | linker | | Location: | 192 - 223 | | Length: | 32 | | Region sequence: |
PASASVSALIGGNQEGSHPQPLGGPEPGPYAQ | | Modification type: | Native
| | PDB: | 2EYZ:A, 2DVJ:A, 2EYW:A, 2EYX:A | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | Modification site
Molecular assembly
Entropic chain
| | Functional subclasses: | Intraprotein interaction
Flexible linkers/spacers
Phosphorylation
Autoregulatory
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; DTT 2 mM; EDTA 1 mM; NaCl 150 mM; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 6 | | Type: | Disordered | | Name: | Inter-SH3 Core (ISC) | | Location: | 224 - 237 | | Length: | 14 | | Region sequence: |
PSVNTPLPNLQNGP | | Modification type: | Native
| | PDB: | 2DVJ:A, 2EYX:A, 2EYZ:A | | Structural/functional type: | Function arises via a disorder to order transition
| | Functional classes: | Molecular assembly
Entropic chain
| | Functional subclasses: | Intraprotein interaction
Flexible linkers/spacers
Autoregulatory
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; DTT 2 mM; EDTA 1 mM; NaCl 150 mM; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 7 | | Type: | Disordered | | Name: | cSH3 | | Location: | 238 - 293 | | Length: | 56 | | Region sequence: |
IYARVIQKRVPNAYDKTALALEVGELVKVTKINVSGQWEGECNGKRGHFPFTHVRL | | Modification type: | Native
| | PDB: | 2EYX:A, 2EYZ:A | | Structural/functional type: | Function arises via a disorder to order transition
| | Functional classes: | Modification site
Molecular assembly
| | Functional subclasses: | Intraprotein interaction
Phosphorylation
Autoregulatory
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; DTT 2 mM; EDTA 1 mM; NaCl 150 mM; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 8 | | Type: | Disordered | | Name: | C-terminal | | Location: | 294 - 304 | | Length: | 11 | | Region sequence: |
LDQQNPDEDFS | | Modification type: | Native
| | PDB: | 2EYX:A, 2EYZ:A | | Structural/functional type: | Relationship to function unknown
| | Functional classes: | Unknown
| | Functional subclasses: | Unknown
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O; Crk-II (PDB 2EYZ is full-length Crk-II, other PDBs are fragments) 0.4 mM; DTT 2 mM; EDTA 1 mM; NaCl 150 mM; Phosphate buffer 20 mM)
- Small-angle X-ray scattering (SAXS) (298 K; pH: 8; Crk-II 20 mg/mL; NaCl 150 mM; Tris-HCl buffer 20 mM)
| References:
- Kobashigawa Y, Sakai M, Naito M, Yokochi M, Kumeta H, Makino Y, Ogura K, Tanaka S, Inagaki F. "Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK." Nat. Struct. Mol. Biol.. 2007; 14(6): 503-10. PubMed: 17515907
| Comments:
|
| Region 9 | | Type: | Disordered | | Name: | DE loop | | Location: | 65 - 85 | | Length: | 21 | | Region sequence: |
SGPRPPVPPSPAQPPPGVSPS | | Modification type: | Fragment
| | PDB: | 1JU5:A | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | Modification site
Molecular recognition effectors
Entropic chain
| | Functional subclasses: | Flexible linkers/spacers
Phosphorylation
Protein-protein binding
| Detection methods:
- Nuclear magnetic resonance (NMR) (303 K; pH: 6.8; 90% H2O/ 10% D2O; Crk SH2 domain fragment (aa S12-R120) (PDB 1JU5) 1.5 mM; sodium azide (0.02%); sodium phosphate 50 mM)
| References:
- Donaldson LW, Gish G, Pawson T, Kay LE, Forman-Kay JD. "Structure of a regulatory complex involving the Abl SH3 domain, the Crk SH2 domain, and a Crk-derived phosphopeptide." Proc. Natl. Acad. Sci. U.S.A.. 2002; 99(22): 14053-8. PubMed: 12384576
| Comments:According to Donaldson et al (2002), the "DE loop" is the flexible linker within the SH2-SH2 domain, and the loop contains an Abl SH3 binding site at G66-P75. The loop also contains phosphorylation sites at S74 and S83, according to UniProt.
|
| References |
- Feller SM, Lewitzky M. "What is in a loop?" Cell Commun. Signal. 2012; 10(1): 31. PubMed: 23110718
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| Comments |
According to Kobashigawa et al (2007), phosphorylation of T221 triggers intramolecular interactions between the SH domains and the hydrophobic Inter-SH3 Core (ISC), resulting in the compact structure of Crk-II. Compare the compact structure of Crk-II with Crk-I [DP00748_A002] which has an extended structure (Crk-I is identical to Crk-II aa 1-203 plus R204 (instead of N204 as in Crk-II)).
Kobashigawa et al (2007) also demonstrated how "amino acid replacement or deletion in the ISC, or disruption of cSH3, disturbs the assembled structure of CRKII."
Feller and Lewitzky (2012) discuss the importance of loops for a variety of protein functions.
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