Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex

Sci Rep. 2014 Jan 10:4:3643. doi: 10.1038/srep03643.

Abstract

LMO2 was discovered via chromosomal translocations in T-cell leukaemia and shown normally to be essential for haematopoiesis. LMO2 is made up of two LIM only domains (thus it is a LIM-only protein) and forms a bridge in a multi-protein complex. We have studied the mechanism of formation of this complex using a single domain antibody fragment that inhibits LMO2 by sequestering it in a non-functional form. The crystal structure of LMO2 with this antibody fragment has been solved revealing a conformational difference in the positioning and angle between the two LIM domains compared with its normal binding. This contortion occurs by bending at a central helical region of LMO2. This is a unique mechanism for inhibiting an intracellular protein function and the structural contusion implies a model in which newly synthesized, intrinsically disordered LMO2 binds to a partner protein nucleating further interactions and suggests approaches for therapeutic targeting of LMO2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Crystallization
  • Crystallography, X-Ray
  • LIM Domain Proteins / chemistry*
  • LIM Domain Proteins / genetics
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / genetics
  • Transcription, Genetic*

Substances

  • Adaptor Proteins, Signal Transducing
  • LIM Domain Proteins
  • LMO2 protein, human
  • Proto-Oncogene Proteins

Associated data

  • PDB/4KFZ