Protein/Protein Interactions (PDZ) in Proximal Tubules

Abstract

IntroductionEssentially all cellular functions rely on the correctspatial organization of proteins. In epithelial cells,this is manifested by a separation of the plasmamembrane into an apical and a basolateral area,which is required for vectorial transport of solutes,and by the formation of junctional complexes toguarantee barrier function. In this article, we sum-marize the current knowledge of PDZ protein-basedmultimeric protein complexes in renal proximaltubular (PT) cells (for definition of the PDZ domain,seebelow), which are involved in the organization ofthe brush border membrane, the basolateral mem-brane and the tight junction of PT cells. In addition,we also consider a fourth subcellular structure, thesubapical compartment (SAC). This compartmenthas been ascribed to the recycling of endocytosedproteins and also to the routing of endocytosedmaterial to the lysosomes.In renal proximal tubules, the majority of filteredsolutes and water are reabsorbed by transepithelialtransport processes and by paracellular pathways[68]. In addition, PT-cells exhibit an exceptionallyhigh rate of endocytosis to recover small peptides andhormones. On a morphological basis, three differentdistinct epithelial cells can be distinguished along theproximal tubules. In the S1 segment, brush bordersare formed by long microvilli, whereas the appear-ance of the microvilli in the S2 and S3 segments is lesspronounced and varies among different species [37].Although this longitudinal morphological heteroge-neity of PT cells is also reflected by functional dif-ferences, in this article, we will not distinguish amongproximal tubular segments, i.e., the PDZ-based pro-tein complexes discussed below are assumed to be ofuniform nature along the entire proximal tubule.ThePDZmoduleNumerous protein domains have been described thatare implicated in protein-protein interactions (see e.g.,www.mshri.on.ca). Based on sequence similarities be-tween the post-synaptic density protein PSD-95, theDrosophilajunctional protein Disc-large and the tightjunctional protein ZO1, one such domain was definedas PDZ. PDZ proteins, among other functions, areprimarily thought to organize large functional unitssuch as synapses [55] or tight junctions [19]. Thecharacteristics of PDZ domains have been reviewedrecently[14,15,28,55]andaresummarizedasfollows:In mammals, over 400 different PDZ proteinshave been identified and grouped into three majorfamilies according to their domain organization:Afirst family encompasses proteins, which only containPDZ domains. The second, MAGUK family (mem-brane-associated guanylate kinases), contains one ormore PDZ domains besides a GuK domain (gua-nylate kinase domain) and a SH3 domain. A thirdfamily was defined containing proteins of multiplePDZ domains together with a variable number ofother protein domains.The PDZ domain comprises between 80 and 90amino-acid residues of which the three-dimensionalstructure has been basically resolved (see http://smart.enbl-heidelberg.de). The building principle is asandwich structure of 6 b-strands and two a-helicesthat form a hydrophobic cleft into which a short pep-tide can be accommodated. As an example, the struc-tural aspect of the CFTR-NHERF interaction hasbeen discussed in detail [38]. In most cases, PDZdomainsbindtoaC-terminalamino-acidmotif.Threedifferent classes of PDZ binding motifs have beenrecognized. They all include the last four C-terminalamino acids, whose characteristics of interaction canbe modulated by more upstream amino acids [55].Besides the classical canonical determinants, addi-tional PDZ binding motifs have been described and