A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

Menglong Zeng; Yuan Shang; Tingfeng Guo; Qinghai He; Wing-Ho Yung; Kai Liu; Mingjie Zhang

doi:10.1073/pnas.1523265113

A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

Menglong Zeng, Yuan Shang, Tingfeng Guo, Qinghai He, Wing-Ho Yung, Kai Liu, Mingjie Zhang^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

38 Citations (Scopus)

Abstract

Shank and SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein) are two highly abundant scaffold proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and in animal models. The molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear, however. Here we report that a sequence preceding the canonical PDZ domain of Shank, together with the elongated PDZ BC loop, form another binding site for a sequence upstream of the SAPAP PDZ-binding motif, leading to a several hundred-fold increase in the affinity of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and the Shank-induced synaptic activity increase. Our study provides a molecular explanation of how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.

Original language	English
Pages (from-to)	E3081-E3090
Journal	PNAS: Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	22
DOIs	https://doi.org/10.1073/pnas.1523265113
Publication status	Published - 31 May 2016
Externally published	Yes

Bibliographical note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Funding

We thank the Shanghai Synchrotron Radiation Facility, beamline BL17U, for the X-ray beam time. This work was supported by the Hong Kong Research Grants Council Grants 663811, 663812, T13-607/12R, AoE-M09-12, and GRF 662012 (to M. Zhang and K.L.); and Ministry of Science and Technology of China 973 Program Grant 2014CB910204 (to M. Zhang). M. Zhang is a Kerry Holdings Professor in Science and a Senior Fellow of the Institute of Advanced Study at Hong Kong University of Science and Technology.

Research Keywords

PDZ
SAPAP
Shank
Specific interaction
Synapse

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RGC-funded

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10.1073/pnas.1523265113

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title = "A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function",

abstract = "Shank and SAPAP (synapse-associated protein 90/postsynaptic density-95-associated protein) are two highly abundant scaffold proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and in animal models. The molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear, however. Here we report that a sequence preceding the canonical PDZ domain of Shank, together with the elongated PDZ BC loop, form another binding site for a sequence upstream of the SAPAP PDZ-binding motif, leading to a several hundred-fold increase in the affinity of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and the Shank-induced synaptic activity increase. Our study provides a molecular explanation of how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.",

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A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function. / Zeng, Menglong; Shang, Yuan; Guo, Tingfeng et al.
In: PNAS: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 22, 31.05.2016, p. E3081-E3090.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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AU - Guo, Tingfeng

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AU - Yung, Wing-Ho

AU - Liu, Kai

AU - Zhang, Mingjie

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A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function

Abstract

Bibliographical note

Funding

Research Keywords

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