Regulation of SR-BI-mediated high-density lipoprotein metabolism by the tissue-specific adaptor protein PDZK1.
OBJECTIVE
A novel mechanism for the regulation of lipoprotein receptor activity is providing new insights into the control of lipid metabolism. The tissue-specific adaptors ARH (autosomal recessive hypercholesterolemia) and PDZK1 [where PDZ derives from postsynaptic density protein (PSD-95)/Drosophila discs-large (dlg)/tight-junction protein (ZO1)] have been shown to control the activities of distinct types of lipoprotein receptors in a posttranscriptional fashion, significantly affecting overall lipoprotein metabolism. This review will focus on one of these lipoprotein receptor-adaptor pairs, the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and its adaptor PDZK1.


RESULTS
The PDZ domain-containing adaptor protein PDZK1 has been shown to bind to and control the activity of the high-density lipoprotein receptor SR-BI via a tissue-specific posttranscriptional mechanism. Mice deficient in PDZK1 have elevated plasma cholesterol levels due to the virtually complete hepatic ablation of SR-BI, implicating PDZK1 as a novel regulator of high-density lipoprotein metabolism.


CONCLUSIONS
The functions of ARH and PDZK1 suggest that other adaptor proteins may be found to control the activities of other cell-surface receptors in a similar tissue-specific fashion. Manipulation of the expression and/or activities of such adaptors might provide new insights into receptor physiology and these adaptors may prove to be attractive targets for pharmaceutical intervention in cholesterol metabolism-related disease processes.
Yesilaltay
Ayce
A
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Kocher
Olivier
O
Rigotti
Attilio
A
Krieger
Monty
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D018955:CD36 Antigens; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D048868:Adaptor Proteins, Signal Transducing; D018955:CD36 Antigens; C500241:Ldlrap1 protein, mouse; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B