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Post-translational modifications in intrinsically disordered regions and their contribution to protein- protein interactions

  • Author(s): Mulvihill, Melinda Michele
  • et al.

Intrinsically disordered regions (IDRs) within proteins have recently been established as having vital functions in both protein recognition and signal transduction. An additional level of complexity is introduced by post- translational modifications, which often times fine-tune the function of IDRs. I have focused on two main systems involving post-translational modifications in IDRs. First, I explored the effect of hydroxylation on the stability and function of IκBα. Contrary to the speculation that the hydroxylation has functional consequences, we did not observe changes in "foldedness" (via H/D exchange mass spectrometry), binding to NF[kappa]B (via surface plasmon resonance), or stability (via proteosome degradation experiments). I also explored the interactions among the IDRs of LRP-CT, AICD, and Fe65, and how post-translational modifications affect these interactions. The intracellular tail of the low-density receptor-related protein (LRP-CT) has been shown to modulate the processing of APP to A[beta], the main component found in Alzheimer's disease brain plaques. The intracellular domain of APP (AICD) and LRP-CT can be linked via the adapter protein Fe65. The PID1 domain of Fe65 can bind LRP-CT and the PID2 domain of Fe65 can bind AICD. The phosphorylation of AICD did not affect the binding of AICD to Fe65, yet the phosphorylation of LRP-CT was necessary for binding to Fe65 and for the trimeric interaction between LRP-CT, Fe65, and AICD to occur. Interestingly, the interaction between the Fe65 PID1 domain and the NPXY motif of LRP-CT is predicted to be phosphorylation-independent because Fe65 PID1 belongs to the Dab-like family of PID domains, in which binding does not depend on phosphorylation. Fe65 PID1 is thus the first Dab-like PID domain identified to bind an NPXY motif in a tyrosine phosphorylation-dependent manner

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