Crystal structure of the tyrosine kinase domain of the human insulin receptor

Hubbard, Stevan R.; Wei, Lei; Ellis, Leland; Hendrickson, Wayne A.

doi:10.1038/372746a0

Cited by 1,076 publications

(896 citation statements)

References 44 publications

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“…In contrast, the activation loop tyrosines are essential for auto-inhibition of the IRK in the absence of ligand (Hubbard et al, 1994). Since TrkA is most closely related to the IRK in the kinase superfamily (Hanks et al, 1988), we assayed the role of the activation loop tyrosines in the mechanism of TrkA activation.…”

Section: Discussionmentioning

confidence: 99%

“…Since TrkA is most closely related to the IRK in the kinase superfamily (Hanks et al, 1988), we assayed the role of the activation loop tyrosines in the mechanism of TrkA activation. Speci®cally, we substituted Y 683 , Y 684 in rat TrkA with acidic amino acids in an e ort to disengage auto-inhibitory interactions with the catalytic base (Hubbard et al, 1994) and drive constitutive kinase activation. Mutant receptors have been expressed in both Cos and nnr5 cells and assayed for intrinsic kinase activity, NGF-independent activation of signaling intermediates and the reconstitution of cell survival and neuritogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest a model of TrkA activation based on crystallographic analyses of the IRK (Hubbard et al, 1994;Hubbard, 1997). Accordingly, Tyr 683 in TrkA is thought to be involved in auto-inhibition of the receptor in the absence of ligand.…”

mentioning

confidence: 85%

“…While the intracellular domain of TrkA has not been crystallized, studies on the b-chain of the IRK (Hubbard et al, 1994;Hubbard, 1997) have provided (Hubbard, 1997). Finally, Tyr 679 in TrkA (Tyr 1158 in the IRK) is predicted to be solvent exposed in an active conformation (Hubbard, 1997) suggesting a possible role in substrate interaction.…”

Section: Autophosphorylation and Biological Responsivenessmentioning

confidence: 99%

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Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-independent cell survival and neuronal differentiation

Gryz

Meakin

2000

Oncogene

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 85%

Section: Autophosphorylation and Biological Responsivenessmentioning

confidence: 99%

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Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-independent cell survival and neuronal differentiation

Gryz

Meakin

2000

Oncogene

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“…The degradation of the E633H and G591A mutant receptors in response to M-CSF was similar to the normal receptor. The straightforward interpretation of this observation is that both the normal and mutant receptors can be downregulated by a ligand-induced change in receptor structure that is independent of receptor kinase Figure 4 The inactive backbone structure of the insulin receptor (Hubbard et al, 1994) showing the location of the indicated amino acids. The activating loop residues 1150 ± 1179 are shown in black.…”

Section: Discussionmentioning

confidence: 99%

Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity

1999

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The downregulation of tyrosine kinase receptors attenuates signalling and is thought to be dependent upon intrinsic receptor kinase activity, largely because downregulation is inhibited by a kinase-inactivating mutation of an invariant lysine residue of the receptors for EGF, insulin, M-CSF and PDGF. We con®rmed that this mutation inhibited the degradation of the M-CSF receptor. However, two di erent kinase inactivating mutations of the invariant amino acids Gly 591 and Glu 633 did not prevent M-CSF-induced receptor degradation, so demonstrating that receptor kinase activity is not essential for this process. Three other kinase-inactivating mutations were found to cause constitutive receptor degradation in the absence of M-CSF, most probably by disrupting the structure of the activating loop of the kinase domain. It is known that extensive movement of the A-loop is necessary for kinase activation and is normally induced by ligand-binding. It is therefore suggested that some aspect or consequence of the change in structure of the A-loop caused by ligand binding also activates receptor downregulation, so ensuring that downregulation is coupled to but is not necessarily dependent upon receptor kinase activity.

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Structural aspects of the functional modules in human protein kinase-Cα deduced from comparative analyses

et al. 1996

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Three-dimensional models of the five functional modules in human protein kinase C alpha (PKC alpha) have been generated on the basis of known related structures. The catalytic region at the C-terminus of the sequence and the N-terminal auto-inhibitory pseudo-substrate have been modeled using the crystal structure complex of cAMP-dependent protein kinase (cAPK) and PKI peptide. While the N-terminal helix of the catalytic region of PKC alpha is predicted to be in a different location compared with cAPK, the C-terminal extension is modeled like that in the cAPK. The predicted permissive phosphorylation site of PKC alpha, Thr 497, is found to be entirely consistent with the mutagenesis studies. Basic Lys and Arg residues in the pseudo-substrate make several specific interactions with acidic residues in the catalytic region and may interact with the permissive phosphorylation site. Models of the two zinc-binding modules of PKC alpha are based on nuclear magnetic resonance and crystal structures of such modules in other PKC isoforms while the calcium phospholipid binding module (C2) is based on the crystal structure of a repeating unit in synaptotagmin I. Phorbol ester binding regions in zinc-binding modules and the calcium binding region in the C2 domain are similar to those in the basis structures. A hypothetical model of the relative positions of all five modules has the putative lipid binding ends of the C2 and the two zinc-binding domains pointing in the same direction and may serve as a basis for further experiments.

show abstract

Crystal structure of the tyrosine kinase domain of the human insulin receptor

Cited by 1,076 publications

References 44 publications

Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-independent cell survival and neuronal differentiation

Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-independent cell survival and neuronal differentiation

Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity

Structural aspects of the functional modules in human protein kinase-Cα deduced from comparative analyses

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