The disordered hypervariable region and the folded catalytic domain of oncogenic K-Ras4B partner in phospholipid binding

Avik Banerjee, Hyunbum Jang, Ruth Nussinov, Vadim Gaponenko*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

37 Scopus citations

Abstract

The C-terminal hypervariable region (HVR) of the splice variant KRAS4B is disordered. Classically, the role of the post-translationally-modified HVR is to navigate Ras in the cell and to anchor it in localized plasma membrane regions. Here, we propose additional regulatory roles, including auto-inhibition by shielding the effector binding site in the GDP-bound state and release upon GTP binding and in the presence of certain oncogenic mutations. The released HVR can interact with calmodulin. We show that oncogenic mutations (G12V/G12D) modulate the HVR-phospholipid binding specificity, resulting in preferential interactions with phosphatidic acid. The shifts in the conformational preferences and binding specificity in the disordered state exemplify the critical role of the unstructured tail of K-Ras4B in cancer.

Original languageEnglish
Pages (from-to)10-17
Number of pages8
JournalCurrent Opinion in Structural Biology
Volume36
DOIs
StatePublished - 1 Feb 2016

Funding

FundersFunder number
National Institutes of HealthHHSN261200800001E
American Cancer SocietyRGS-09-057-01-GMC
National Heart, Lung, and Blood InstituteR21HL118588
National Cancer InstituteR01 CA135341, R01 CA188427

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