AI Article Synopsis

  • * The stability and functionality of sPDZD2 were studied, revealing a folding pathway with a transient intermediate caused by the denaturation of its PDZ domains.
  • * This intermediate demonstrates a stronger binding affinity to its physiological ligand compared to the native state, suggesting a hidden functional role that goes beyond what is typically observed in the native configuration.

Article Abstract

PDZ domains are the most diffused protein-protein interaction modules of the human proteome and are often present in tandem repeats. An example is PDZD2, a protein characterized by the presence of six PDZ domains that undergoes a proteolytic cleavage producing sPDZD2, comprising a tandem of two PDZ domains, namely PDZ5 and PDZ6. Albeit the physiopathological importance of sPDZD2 is well-established, the interaction with endogenous ligands has been poorly characterized. To understand the determinants of the stability and function of sPDZD2, we investigated its folding pathway. Our data highlights the presence of a complex scenario involving a transiently populated folding intermediate that may be accumulated from the concurrent denaturation of both PDZ5 and PDZ6 domains. Importantly, double jump kinetic experiments allowed us to pinpoint the ability of this transient intermediate to bind the physiological ligand of sPDZD2 with increased affinity compared to the native state. In summary, our results provide an interesting example of a functionally competent misfolded intermediate, which may exert a cryptic function that is not captured from the analysis of the native state only.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9375522PMC
http://dx.doi.org/10.1002/pro.4396DOI Listing

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