MPP1 links the Usher protein network and the Crumbs protein complex in the retina.
The highly ordered distribution of neurons is an essential feature of a functional mammalian retina. Disruptions in the apico-basal polarity complexes at the outer limiting membrane (OLM) of the retina are associated with retinal patterning defects in vertebrates. We have analyzed the binding repertoire of MPP5/Pals1, a key member of the apico-basal Crumbs polarity complex, that has functionally conserved counterparts in zebrafish (nagie oko) and Drosophila (Stardust). We show that MPP5 interacts with its MAGUK family member MPP1/p55 at the OLM. Mechanistically, this interaction involves heterodimerization of both MAGUK modules in a directional fashion. MPP1 expression in the retina throughout development resembles the expression of whirlin, a multi-PDZ scaffold protein and an important organizer in the Usher protein network. We demonstrate that both proteins interact strongly by both a classical PDZ domain-to-PDZ binding motif (PBM) mechanism, and a mechanism involving internal epitopes. MPP1 and whirlin colocalize in the retina at the OLM, at the outer synaptic layer and at the basal bodies and the ciliary axoneme. In view of the known roles of the Crumbs and Usher protein networks, our findings suggest a novel link of the core developmental processes of actin polymerization and establishment/maintenance of apico-basal cell polarity through MPP1. These processes, essential in neural development and patterning of the retina, may be disrupted in eye disorders that are associated with defects in these protein networks.
Gosens
Ilse
I
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
van Wijk
Erwin
E
Kersten
Ferry F J
FF
Krieger
Elmar
E
van der Zwaag
Bert
B
Märker
Tina
T
Letteboer
Stef J F
SJ
Dusseljee
Simone
S
Peters
Theo
T
Spierenburg
Henk A
HA
Punte
Ingrid M
IM
Wolfrum
Uwe
U
Cremers
Frans P M
FP
Kremer
Hannie
H
Roepman
Ronald
R
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D001798:Blood Proteins; C448939:CRB1 protein, human; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; C089465:MPP1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C477219:WHRN protein, human; D009703:Nucleoside-Phosphate Kinase; C501307:MPP5 protein, human