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Protein Kinases

Protein Kinases . Lampros Mavrogiannis (Newcastle 10/01/2008). The Protein Kinase Motif: Structure . Ancient eukaryotic motif. typically ~250 aa long. Two distinct domains . Cleft for substrate binding . Provides a conserved framework but also flexibility.

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Protein Kinases

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  1. Protein Kinases Lampros Mavrogiannis (Newcastle 10/01/2008)

  2. The Protein Kinase Motif: Structure Ancient eukaryotic motif typically ~250 aa long Two distinct domains Cleft for substrate binding Provides a conserved framework but also flexibility

  3. The Protein Kinase Motif: Structure Human CDK2 Bound ATP Active conformation

  4. The Protein Kinase Motif: Function Active site Specific residues and loops that may interact with ATP, target protein, or self Inactive conformation varies, but the active conformation is very similar Surface plasticity enables recognition of diverse targets Regulation Protein-protein interactions, phosphorylation Fusion with other motifs

  5. The Protein Kinase Motif: Genomics & Evolution Human complement ~500 genes 7 well-defined sub-classes Others Tyr kinase (TK) Tyr kinase-like (TKL) Yeast sterile homologues (STE) Casein kinase 1 (CK1) PKA, PKG, PKC (AGC) Calcium/calmodulin-dependent kinases (CMK) CDK, MAPK, GSK3, CLK (CMGC) hard to classify atypical kinase motifs enzyme function lost pseudogenes

  6. The Protein Kinase Motif: Genomics & Evolution

  7. The Protein Kinase Motif: Biological Roles Cellular processes Intercellular communication Developmental decisions Cell cycle progression Cytoskeletal rearrangements Metabolism control Evolutionary reflections Expansions of certain families in mammals

  8. Examples: RET Biology Receptor Tyr kinase, binds GDNF ligands – receptor complexes, MAP kinase cascade downstream Clinical spectrum Multiple endocrine neoplasia type 2 (MEN2A, MEN2B, familial medulary thyroid carcinoma) Hirschsprung disease Mutation spectrum MEN2A – missense changes in certain extracellular Cys residues (gain-of-function) MEN2B – Met918Thr in kinase motif (gain-of-function) Hirschsprung disease – diffuse, including kinase motif (haploinsufficiency)

  9. Examples: ACVRL1 (ALK1) Biology Type I receptor Ser/Thr kinase, binds TGFβ ligands – endothelin complexes, signals through Smads Clinical spectrum Hereditary haemorrhagic telangiectasia type 2 Mutation spectrum Random, but most mutations in kinase motif (haploinsufficiency)

  10. Examples: MAP2K1 (MEK1) Biology MAP kinase-kinase (Thr/Tyr) kinase, sits between BRAF and ERK Clinical spectrum One of the genes for cardiofaciocutaneous syndrome Mutation spectrum Few mutations reported so far, one in kinase domain (gain-of-function)

  11. Examples: PRKCG Biology Member of the protein kinase C family Clinical spectrum Spinocerebellar ataxia 14 Mutation spectrum Mutations in the kinase motif associated with broader neurological phenotype (unclear mechanism)

  12. Examples: STK11 (LKB1) Biology Ser/Thr kinase Clinical spectrum Peutz-Jeghers syndrome Mutation spectrum Random, both truncating and missense mutations affecting the kinase motif (loss-of-function, probably haploinsufficiency)

  13. Examples: CDK4 Biology Ser kinase implicated in the G1 checkpoint Interacts with D cyclins and CDKN2A (p16) Clinical spectrum Minor gene for familial malignant melanoma Mutation spectrum Missense changes affecting Arg24 only within the kinase motif (gain-of-function through loss of p16 inhibition)

  14. Recent Reviews Manning, G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002;298:1912-34 Manning G, Plowman GD, Hunter T, Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 2002;27:514-20 Protein Kinase Resources http://www.kinase.com http://www.kinasenet.org

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