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Field	Query

	Field	Term

General Information:

Id:	7,255 (click here to show other Interactions for entry)
Diseases:	Alzheimer disease - [OMIM] Metabolic
Organism:	Mammalia
Publication type:	review
Reference:	Phillips MC(2014) Apolipoprotein E isoforms and lipoprotein metabolism IUBMB Life 66: 616-623 [PMID: 25328986]

Interaction Information:

Comment	APOE4: Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms (APOE2, APOE3, APOE4) and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol / high density lipoprotein-cholesterol ratio). ApoE3 contains cysteine (Cys) at position 112 and Arg at position at 158, whereas apoE2 and apoE4 contains Cys and Arg, respectively, at both sites. ApoE3 and apoE4 bind to the LDLR with similarly high affinity but the binding of apoE2 is some two orders of magnitude weaker.
Formal Description Interaction-ID: 71375	gene/protein mutant APOE (isoform E4) increases_activity of phenotype abnormal circulating lipid level

Comment	APOE4: Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms (APOE2, APOE3, APOE4) and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol / high density lipoprotein-cholesterol ratio). ApoE3 contains cysteine (Cys) at position 112 and Arg at position at 158, whereas apoE2 and apoE4 contains Cys and Arg, respectively, at both sites. ApoE3 and apoE4 bind to the LDLR with similarly high affinity but the binding of apoE2 is some two orders of magnitude weaker.
Formal Description Interaction-ID: 71388	gene/protein mutant APOE (isoform E4) affects_activity of process low-density lipoprotein particle receptor binding Binding of APOE4 to the LDLR is unaffected

Comment	APOE4: Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms (APOE2, APOE3, APOE4) and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol / high density lipoprotein-cholesterol ratio). ApoE3 contains cysteine (Cys) at position 112 and Arg at position at 158, whereas apoE2 and apoE4 contains Cys and Arg, respectively, at both sites. ApoE3 and apoE4 bind to the LDLR with similarly high affinity but the binding of apoE2 is some two orders of magnitude weaker.
Formal Description Interaction-ID: 71391	gene/protein mutant APOE (isoform E4) increases_activity of process lipid binding The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability.

Comment	APOE4: Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms (APOE2, APOE3, APOE4) and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol / high density lipoprotein-cholesterol ratio). ApoE3 contains cysteine (Cys) at position 112 and Arg at position at 158, whereas apoE2 and apoE4 contains Cys and Arg, respectively, at both sites. ApoE3 and apoE4 bind to the LDLR with similarly high affinity but the binding of apoE2 is some two orders of magnitude weaker.
Formal Description Interaction-ID: 71392	gene/protein mutant APOE (isoform E4) increases_activity of process very-low-density lipoprotein particle binding The strong lipid binding ability of apoE4 is the basis for the preferential binding of this isoform to VLDL particles, the surfaces of which are about 60% PL-covered. ApoE4 binds much better than apoE3 to VLDL but somewhat less well than apoE3 to HDL.

Comment	ApoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol / high density lipoprotein-cholesterol ratio).
Formal Description Interaction-ID: 71394	gene/protein mutant APOE (isoform E4) increases_activity of phenotype alatered VLDL lipolytic processing ApoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation.

Comment	ApoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol / high density lipoprotein-cholesterol ratio).
Formal Description Interaction-ID: 71403	gene/protein mutant APOE (isoform E4) increases_activity of phenotype increased pro-atherogenic lipoprotein-cholesterol distribution

Comment	In mice expressing either human apoE3 or apoE4 expression of apoE4 is associated with higher VLDL-cholesterol and incidence of atherosclerosis.
Formal Description Interaction-ID: 71423	gene/protein mutant APOE (isoform E4) increases_activity of phenotype increased circulating VLDL cholesterol level in transgenic mouse, in plasma

Comment	In mice expressing either human apoE3 or apoE4 expression of apoE4 is associated with higher VLDL-cholesterol and incidence of atherosclerosis.
Formal Description Interaction-ID: 71430	gene/protein mutant APOE (isoform E4) increases_activity of phenotype increased susceptibility to atherosclerosis in transgenic mouse, in plasma

Comment	Hypercholesterolemia is associated with apoE4.
Formal Description Interaction-ID: 71431	gene/protein mutant APOE (isoform E4) increases_activity of phenotype increased circulating cholesterol level

Comment	ApoE4 binds much better than apoE3 to VLDL but somewhat less well than apoE3 to HDL.
Formal Description Interaction-ID: 71436	gene/protein mutant APOE (isoform E4) decreases_activity of process high-density lipoprotein particle binding compared to apoE3; ApoE4 binds much better than apoE3 to VLDL but somewhat less well than apoE3 to HDL

Comment	ApoE4 binds more to VLDL because of its higher lipid affinity leading to inhibition of lipolysis (probably because of displacement of apoC-II) so that, at the same apoE expression level of ApoE3 and ApoE4, progression down the lipolysis cascade is relatively limited in the case of apoE4.
Formal Description Interaction-ID: 71448	gene/protein mutant APOE (isoform E4) decreases_activity of process lipid catabolic process ApoE4 binds more to VLDL because of its higher lipid affinity leading to inhibition of lipolysis

Comment	ApoE4 binds more to VLDL because of its higher lipid affinity leading to inhibition of lipolysis (probably because of displacement of apoC-II) so that, at the same apoE expression level of ApoE3 and ApoE4, progression down the lipolysis cascade is relatively limited in the case of apoE4.
Formal Description Interaction-ID: 111429	gene/protein mutant APOE (isoform E4) interacts (colocalizes) with complex/PPI VLDL ApoE4 binds more to VLDL because of its higher lipid affinity leading to inhibition of lipolysis

Comment	Hypercholesterolemia is associated with apoE4.
Formal Description Interaction-ID: 113458	gene/protein mutant APOE (isoform E4) decreases_activity of process cholesterol homeostasis resulting in Hypercholesterolemia

Comment	ApoE4 binds more to VLDL because of its higher lipid affinity leading to inhibition of lipolysis (probably because of displacement of apoC-II) so that, at the same apoE expression level of ApoE3 and ApoE4, progression down the lipolysis cascade is relatively limited in the case of apoE4.
Formal Description Interaction-ID: 114524	gene/protein mutant APOE (isoform E4) decreases_activity of process VLDL lipid catabolic process ApoE4 binds more to VLDL because of its higher lipid affinity leading to inhibition of lipolysis

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