The Structural Basis for Autoinhibition of FLT3 by the Juxtamembrane Domain

Mol Cell. 2004 Jan 30;13(2):169-78. doi: 10.1016/s1097-2765(03)00505-7.

Abstract

FLT3 is a type III receptor tyrosine kinase that is thought to play a key role in hematopoiesis. Certain classes of FLT3 mutations cause constitutively activated forms of the receptor that are found in significant numbers of patients with acute myelogenous leukemia (AML). The mutations occur either in the activation loop, for example, as point mutations of Asp835 or as internal tandem duplication (ITD) sequences in the juxtamembrane (JM) domain. To further understand the nature of FLT3 autoinhibition and regulation, we have determined the crystal structure of the autoinhibited form of FLT3. This structure shows the autoinhibitory conformation of a complete JM domain in this class of receptor tyrosine kinases. The detailed inhibitory mechanism of the JM domain is revealed, which is likely utilized by other members of type III receptor tyrosine kinases.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cloning, Molecular
  • Gene Library
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Point Mutation
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / physiology*
  • Receptor Protein-Tyrosine Kinases / chemistry*
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Sequence Homology, Amino Acid
  • fms-Like Tyrosine Kinase 3

Substances

  • Proto-Oncogene Proteins
  • FLT3 protein, human
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3

Associated data

  • PDB/1RJB