PMID- 29961325
OWN - NLM
STAT- MEDLINE
DCOM- 20190725
LR  - 20210504
IS  - 1520-5207 (Electronic)
IS  - 1520-6106 (Print)
IS  - 1520-5207 (Linking)
VI  - 122
IP  - 30
DP  - 2018 Aug 2
TI  - Arl2-Mediated Allosteric Release of Farnesylated KRas4B from Shuttling Factor 
      PDEdelta.
PG  - 7503-7513
LID - 10.1021/acs.jpcb.8b04347 [doi]
AB  - Proper localization of Ras proteins at the plasma membrane (PM) is crucial for 
      their functions. To get to the PM, KRas4B and some other Ras family proteins bind 
      to the PDEdelta shuttling protein through their farnesylated hypervariable regions 
      (HVRs). The docking of their farnesyl (and to a lesser extent geranylgeranyl) in 
      the hydrophobic pocket of PDEdelta's stabilizes the interaction. At the PM, guanosine 
      5'-triphosphate (GTP)-bound Arf-like protein 2 (Arl2) assists in the release of 
      Ras from the PDEdelta. However, exactly how is still unclear. Using all-atom 
      molecular dynamics simulations, we unraveled the detailed mechanism of 
      Arl2-mediated release of KRas4B, the most abundant oncogenic Ras isoform, from 
      PDEdelta. We simulated ternary Arl2-PDEdelta-KRas4B HVR complexes and observed that Arl2 
      binding weakens the PDEdelta-farnesylated HVR interaction. Our detailed analysis 
      showed that allosteric changes (involving beta6 of PDEdelta and additional PDEdelta 
      residues) compress the hydrophobic PDEdelta pocket and push the HVR out. Mutating 
      PDEdelta residues that mediate allosteric changes in PDEdelta terminates the release 
      process. Mutant Ras proteins are enriched in human cancers, with currently no 
      drugs in the clinics. This mechanistic account may inspire efforts to develop 
      drugs suppressing oncogenic KRas4B release.
FAU - Ozdemir, E Sila
AU  - Ozdemir ES
FAU - Jang, Hyunbum
AU  - Jang H
AUID- ORCID: 0000-0001-9402-4051
AD  - Cancer and Inflammation Program , Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, National Cancer Institute at Frederick , 
      Frederick , Maryland 21702 , United States.
FAU - Gursoy, Attila
AU  - Gursoy A
AUID- ORCID: 0000-0002-2297-2113
FAU - Keskin, Ozlem
AU  - Keskin O
FAU - Nussinov, Ruth
AU  - Nussinov R
AD  - Cancer and Inflammation Program , Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, National Cancer Institute at Frederick , 
      Frederick , Maryland 21702 , United States.
AD  - Department of Human Molecular Genetics and Biochemistry , Sackler School of 
      Medicine, Tel Aviv University , Tel Aviv 69978 , Israel.
LA  - eng
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - Z01 BC010440/ImNIH/Intramural NIH HHS/United States
GR  - Z01 BC010441/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180718
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6)
RN  - EC 3.6.1.- (ARL2 protein, human)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
MH  - Allosteric Regulation
MH  - Cell Membrane/chemistry/metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 6/*chemistry/metabolism
MH  - GTP-Binding Proteins/*chemistry/metabolism
MH  - Humans
MH  - Hydrophobic and Hydrophilic Interactions
MH  - Molecular Dynamics Simulation
MH  - Mutation
MH  - Protein Binding
MH  - Protein Prenylation
MH  - Proto-Oncogene Proteins p21(ras)/*chemistry/genetics/metabolism
PMC - PMC8087113
MID - NIHMS1683797
EDAT- 2018/07/03 06:00
MHDA- 2019/07/26 06:00
PMCR- 2021/04/30
CRDT- 2018/07/03 06:00
PHST- 2018/07/03 06:00 [pubmed]
PHST- 2019/07/26 06:00 [medline]
PHST- 2018/07/03 06:00 [entrez]
PHST- 2021/04/30 00:00 [pmc-release]
AID - 10.1021/acs.jpcb.8b04347 [doi]
PST - ppublish
SO  - J Phys Chem B. 2018 Aug 2;122(30):7503-7513. doi: 10.1021/acs.jpcb.8b04347. Epub 
      2018 Jul 18.