PMID- 7994571
OWN - NLM
STAT- MEDLINE
DCOM- 19950119
LR  - 20190914
IS  - 0969-2126 (Print)
IS  - 0969-2126 (Linking)
VI  - 2
IP  - 8
DP  - 1994 Aug 15
TI  - Salt bridge relay triggers defective LDL receptor binding by a mutant 
      apolipoprotein.
PG  - 713-8
AB  - BACKGROUND: Apolipoprotein-E (apo-E), a 34kDa blood plasma protein, plays a key 
      role in directing cholesterol transport via its interaction with the low density 
      lipoprotein (LDL) receptor. The amino-terminal domain of apo-E forms an unusually 
      elongated four-helix bundle arranged such that key basic residues involved in LDL 
      receptor binding form a cluster at the end of one of the helices. A common apo-E 
      variant, apo-E2, corresponding to the single-site substitution Arg158-->Cys, 
      displays minimal LDL receptor binding and is associated with significant changes 
      in plasma cholesterol levels and increased risk of coronary heart disease. 
      Surprisingly, the site of mutation in this variant is physically well removed (> 
      12A) from the cluster of LDL receptor binding residues. RESULTS: We now report 
      the refined crystal structure of the amino-terminal domain of apo-E2, at a 
      nominal resolution of 3.0A. This structure reveals significant conformational 
      changes relative to the wild-type protein that may account for reduced LDL 
      receptor binding. Removal of the Arg158 side chain directly disrupts a pair of 
      salt bridges, causing a compensatory reorganization of salt bridge partners that 
      dramatically alters the charge surface presented by apo-E to its receptor. 
      CONCLUSIONS: It is proposed that the observed reorganization of surface salt 
      bridges is responsible for the decreased receptor binding by apo-E2. This 
      reorganization, essentially functioning as a mutationally induced electrostatic 
      switch to turn off receptor binding, represents a novel mechanism for the 
      propagation of conformational changes over significant distances.
FAU - Wilson, C
AU  - Wilson C
AD  - Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, 
      University of California, San Francisco 94143-0448.
FAU - Mau, T
AU  - Mau T
FAU - Weisgraber, K H
AU  - Weisgraber KH
FAU - Wardell, M R
AU  - Wardell MR
FAU - Mahley, R W
AU  - Mahley RW
FAU - Agard, D A
AU  - Agard DA
LA  - eng
GR  - HL41633/HL/NHLBI NIH HHS/United States
GR  - RR-1081/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Structure
JT  - Structure (London, England : 1993)
JID - 101087697
RN  - 0 (Apolipoprotein E2)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, LDL)
SB  - IM
MH  - Apolipoprotein E2
MH  - Apolipoproteins E/*chemistry/genetics/metabolism
MH  - Computer Simulation
MH  - Crystallography
MH  - Humans
MH  - Models, Molecular
MH  - *Mutation
MH  - Peptide Fragments/*chemistry/genetics/metabolism
MH  - *Protein Conformation
MH  - Receptors, LDL/*metabolism
EDAT- 1994/08/15 00:00
MHDA- 1994/08/15 00:01
CRDT- 1994/08/15 00:00
PHST- 1994/08/15 00:00 [pubmed]
PHST- 1994/08/15 00:01 [medline]
PHST- 1994/08/15 00:00 [entrez]
AID - S0969-2126(00)00072-1 [pii]
AID - 10.1016/s0969-2126(00)00072-1 [doi]
PST - ppublish
SO  - Structure. 1994 Aug 15;2(8):713-8. doi: 10.1016/s0969-2126(00)00072-1.