p600 stabilizes microtubules to prevent the aggregation of CaMKIIα during photoconductive stimulation

Belzil, Camille; Ramos, Tim; Sanada, Kamon; Colicos, Michael A.; Nguyen, Minh Dang

doi:10.2478/s11658-014-0201-9

Cited by 4 publications

(1 citation statement)

References 34 publications

(55 reference statements)

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“…Receptor tyrosine kinase environments are largely similar to the slit-diaphragm protein complex, which is orchestrated by tyrosine phosphorylation of Fn3 domain-containing proteins (32,33). In addition, Ubr4 has been implicated in various functions including localization and turnover of membrane channels in neurons or axon guidance (27,34). Knock-out of this protein in mice causes an embryonically lethal phenotype, mainly via disruption of vascular development and yolk sack defects (29).…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes

Rinschen¹,

Bharill

et al. 2016

Hum. Mol. Genet.

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The PHB-domain protein podocin maintains the renal filtration barrier and its mutation is an important cause of hereditary nephrotic syndrome. Podocin and its Caenorhabditis elegans orthologue MEC-2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the podocyte slit diaphragm, MEC-2 is found in neurons required for touch sensitivity. Here, we show that the ubiquitin ligase Ubr4 is a key component of the podocin interactome purified both from cultured podocytes and native glomeruli. It colocalizes with podocin and regulates its stability. In C. elegans, this process is conserved. Here, Ubr4 is responsible for the degradation of mislocalized MEC-2 multimers. Ubiquitylomic analysis of mouse glomeruli revealed that podocin is ubiquitylated at two lysine residues. These sites were Ubr4-dependent and were conserved across species. Molecular dynamics simulations revealed that ubiquitylation of one site, K301, do not only target podocin/MEC-2 for proteasomal degradation, but may also affect stability and disassembly of the multimeric complex. We suggest that Ubr4 is a key regulator of podocyte foot process proteostasis.

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