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SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region

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SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. / Mameza, Marie Germaine; Dvoretskova, Elena; Bamann, Margarete; Hönck, Hans-Hinrich; Güler, Türkan; Boeckers, Tobias M; Schoen, Michael; Verpelli, Chiara; Sala, Carlo; Barsukov, Igor; Dityatev, Alexander; Kreienkamp, Hans-Jürgen.

In: J BIOL CHEM, Vol. 288, No. 37, 13.09.2013, p. 26697-708.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Mameza, MG, Dvoretskova, E, Bamann, M, Hönck, H-H, Güler, T, Boeckers, TM, Schoen, M, Verpelli, C, Sala, C, Barsukov, I, Dityatev, A & Kreienkamp, H-J 2013, 'SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region', J BIOL CHEM, vol. 288, no. 37, pp. 26697-708. https://doi.org/10.1074/jbc.M112.424747

APA

Mameza, M. G., Dvoretskova, E., Bamann, M., Hönck, H-H., Güler, T., Boeckers, T. M., Schoen, M., Verpelli, C., Sala, C., Barsukov, I., Dityatev, A., & Kreienkamp, H-J. (2013). SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. J BIOL CHEM, 288(37), 26697-708. https://doi.org/10.1074/jbc.M112.424747

Vancouver

Mameza MG, Dvoretskova E, Bamann M, Hönck H-H, Güler T, Boeckers TM et al. SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. J BIOL CHEM. 2013 Sep 13;288(37):26697-708. https://doi.org/10.1074/jbc.M112.424747

Bibtex

@article{80e5b9398c894c38852e7706ca115602,
title = "SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region",
abstract = "Shank/ProSAP proteins are major scaffold proteins of the postsynaptic density; mutations in the human SHANK3 gene are associated with intellectual disability or autism spectrum disorders. We have analyzed the functional relevance of several SHANK3 missense mutations affecting the N-terminal portion of the protein by expression of wild-type and mutant Shank3 in cultured neurons and by binding assays in heterologous cells. Postsynaptic targeting of recombinant Shank3 was unaltered. In electrophysiological experiments, both wild-type and L68P mutant forms of Shank3 were equally effective in restoring synaptic function after knockdown of endogenous Shank3. We observed that several mutations affected binding to interaction partners of the Shank3 ankyrin repeat region. One of these mutations, L68P, improved binding to both ligands. Leu-68 is located N-terminal to the ankyrin repeats, in a highly conserved region that we identify here as a novel domain termed the Shank/ProSAP N-terminal (SPN) domain. We show that the SPN domain interacts with the ankyrin repeats in an intramolecular manner, thereby restricting access of either Sharpin or α-fodrin. The L68P mutation disrupts this blockade, thus exposing the Shank3 ankyrin repeat region to its ligands. Our data identify a new type of regulation of Shank proteins and suggest that mutations in the SHANK3 gene do not necessarily induce a loss of function, but may represent a gain of function with respect to specific interaction partners.",
keywords = "Animals, Ankyrin Repeat, Autistic Disorder, Carrier Proteins, Electrophysiology, HEK293 Cells, Hippocampus, Humans, Leucine, Ligands, Mice, Mice, Inbred C57BL, Microfilament Proteins, Mutation, Missense, Nerve Tissue Proteins, Neurons, Patch-Clamp Techniques, Protein Binding, Protein Structure, Tertiary, Rats, Synaptic Transmission, Two-Hybrid System Techniques, Ubiquitins",
author = "Mameza, {Marie Germaine} and Elena Dvoretskova and Margarete Bamann and Hans-Hinrich H{\"o}nck and T{\"u}rkan G{\"u}ler and Boeckers, {Tobias M} and Michael Schoen and Chiara Verpelli and Carlo Sala and Igor Barsukov and Alexander Dityatev and Hans-J{\"u}rgen Kreienkamp",
year = "2013",
month = sep,
day = "13",
doi = "10.1074/jbc.M112.424747",
language = "English",
volume = "288",
pages = "26697--708",
journal = "J BIOL CHEM",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "37",

}

RIS

TY - JOUR

T1 - SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region

AU - Mameza, Marie Germaine

AU - Dvoretskova, Elena

AU - Bamann, Margarete

AU - Hönck, Hans-Hinrich

AU - Güler, Türkan

AU - Boeckers, Tobias M

AU - Schoen, Michael

AU - Verpelli, Chiara

AU - Sala, Carlo

AU - Barsukov, Igor

AU - Dityatev, Alexander

AU - Kreienkamp, Hans-Jürgen

PY - 2013/9/13

Y1 - 2013/9/13

N2 - Shank/ProSAP proteins are major scaffold proteins of the postsynaptic density; mutations in the human SHANK3 gene are associated with intellectual disability or autism spectrum disorders. We have analyzed the functional relevance of several SHANK3 missense mutations affecting the N-terminal portion of the protein by expression of wild-type and mutant Shank3 in cultured neurons and by binding assays in heterologous cells. Postsynaptic targeting of recombinant Shank3 was unaltered. In electrophysiological experiments, both wild-type and L68P mutant forms of Shank3 were equally effective in restoring synaptic function after knockdown of endogenous Shank3. We observed that several mutations affected binding to interaction partners of the Shank3 ankyrin repeat region. One of these mutations, L68P, improved binding to both ligands. Leu-68 is located N-terminal to the ankyrin repeats, in a highly conserved region that we identify here as a novel domain termed the Shank/ProSAP N-terminal (SPN) domain. We show that the SPN domain interacts with the ankyrin repeats in an intramolecular manner, thereby restricting access of either Sharpin or α-fodrin. The L68P mutation disrupts this blockade, thus exposing the Shank3 ankyrin repeat region to its ligands. Our data identify a new type of regulation of Shank proteins and suggest that mutations in the SHANK3 gene do not necessarily induce a loss of function, but may represent a gain of function with respect to specific interaction partners.

AB - Shank/ProSAP proteins are major scaffold proteins of the postsynaptic density; mutations in the human SHANK3 gene are associated with intellectual disability or autism spectrum disorders. We have analyzed the functional relevance of several SHANK3 missense mutations affecting the N-terminal portion of the protein by expression of wild-type and mutant Shank3 in cultured neurons and by binding assays in heterologous cells. Postsynaptic targeting of recombinant Shank3 was unaltered. In electrophysiological experiments, both wild-type and L68P mutant forms of Shank3 were equally effective in restoring synaptic function after knockdown of endogenous Shank3. We observed that several mutations affected binding to interaction partners of the Shank3 ankyrin repeat region. One of these mutations, L68P, improved binding to both ligands. Leu-68 is located N-terminal to the ankyrin repeats, in a highly conserved region that we identify here as a novel domain termed the Shank/ProSAP N-terminal (SPN) domain. We show that the SPN domain interacts with the ankyrin repeats in an intramolecular manner, thereby restricting access of either Sharpin or α-fodrin. The L68P mutation disrupts this blockade, thus exposing the Shank3 ankyrin repeat region to its ligands. Our data identify a new type of regulation of Shank proteins and suggest that mutations in the SHANK3 gene do not necessarily induce a loss of function, but may represent a gain of function with respect to specific interaction partners.

KW - Animals

KW - Ankyrin Repeat

KW - Autistic Disorder

KW - Carrier Proteins

KW - Electrophysiology

KW - HEK293 Cells

KW - Hippocampus

KW - Humans

KW - Leucine

KW - Ligands

KW - Mice

KW - Mice, Inbred C57BL

KW - Microfilament Proteins

KW - Mutation, Missense

KW - Nerve Tissue Proteins

KW - Neurons

KW - Patch-Clamp Techniques

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Rats

KW - Synaptic Transmission

KW - Two-Hybrid System Techniques

KW - Ubiquitins

U2 - 10.1074/jbc.M112.424747

DO - 10.1074/jbc.M112.424747

M3 - SCORING: Journal article

C2 - 23897824

VL - 288

SP - 26697

EP - 26708

JO - J BIOL CHEM

JF - J BIOL CHEM

SN - 0021-9258

IS - 37

ER -