Molecular Complexes Formed with Polycystins

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Abstract

Polycystins are a family of novel transmembrane proteins with at least six members already identified in humans. Defects in polycystins-1 and -2 are responsible for nearly all cases of autosomal-dominant polycystic kidney disease (ADPKD), a major cause of end-stage renal failure. With the progress made in elucidating the genetic basis of ADPKD, the challenges are to understand the functions of polycystins and to delineate the biochemical and cellular mechanisms of cyst development and progression. In this review, we summarize the recent advances in our knowledge of the functions of polycystins with emphasis on the molecular composition of polycystin protein complexes in the kidney.

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Most cited references 25

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Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.

K Hanaoka, F Qian, A Boletta … (2001)

The human kidney is composed of roughly 1.2-million renal tubules that must maintain their tubular structure to function properly. In autosomal dominant polycystic kidney disease (ADPKD) cysts develop from renal tubules and enlarge independently, in a process that ultimately causes renal failure in 50% of affected individuals. Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown. PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell-cell or cell-matrix interactions, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein. Here we show that polycystin-1 and -2 interact to produce new calcium-permeable non-selective cation currents. Neither polycystin-1 nor -2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization do not result in new channel activity. We also show that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 co-assemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function.

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Autosomal dominant polycystic kidney disease.

Aaron Gabow (1993)

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Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.

G Walz, L Tsiokas, Stanley E Kim … (1997)

PKD1 and PKD2 are two recently identified genes that are responsible for the vast majority of autosomal polycystic kidney disease, a common inherited disease that causes progressive renal failure. PKD1 encodes polycystin, a large glycoprotein that contains several extracellular motifs indicative of a role in cell-cell or cell-matrix interactions, and the PKD2 encodes a protein with homology to a voltage-activated calcium channel and to PKD1. It is currently unknown how mutations of either protein functionally cause autosomal polycystic kidney disease. We show that PKD1 and PKD2 interact through their C-terminal cytoplasmic tails. This interaction resulted in an up-regulation of PKD1 but not PKD2. Furthermore, the cytoplasmic tail of PKD2 but not PKD1 formed homodimers through a coiled-coil domain distinct from the region required for interaction with PKD1. These interactions suggest that PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis and that PKD1 may require the presence of PKD2 for stable expression.

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Author and article information

Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2003

Publication date (Print): January 2003

Publication date (Electronic): 17 November 2004

Volume: 93

Issue: 1

Pages: e3-e8

Affiliations

Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass., USA

Article

Publisher ID: 66648 Other ID: Nephron Exp Nephrol 2003;93:e3–e8

DOI: 10.1159/000066648

PubMed ID: 12411743

SO-VID: 763bd033-03cc-4fe4-ab43-39b02e5c06fd

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 10 February 2002

Date accepted : 18 April 2002

Page count

Figures: 1, Tables: 1, References: 53, Pages: 1

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Molecular Complexes Formed with Polycystins

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Abstract

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Karger: Nephrology

Most cited references 25

Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.

Autosomal dominant polycystic kidney disease.

Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.

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