Raquel M. Melero-Fernandez de Mera

University of Eastern Finland

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Lili Li

Xinjiang Academy of Agricultural Sciences

Michael J. Courtney

Åbo Akademi University

Arkadiusz Popinigis

Turku Centre for Biotechnology

Riikka Kärnä

University of Eastern Finland

Leena Yadav

University of Helsinki

Nael Nadif Kasri

Radboud University Nijmegen

Davide Vigetti

University of Insubria

Jia Chen

Capital Medical University

Markku Tammi

University of Eastern Finland

Wei Ba

Imperial College London

Cooperative Institutions

University of Eastern Finland

University of Turku

Finland University

Åbo Akademi University

Institute for Biomedicine

Turku Centre for Biotechnology

University of Helsinki

Radboud University Nijmegen

Radboud University Medical Center

Netherlands Institute for Neuroscience

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Effects of mutations in the post-translational modification sites on the trafficking of hyaluronan synthase 2 (HAS2)

Matrix Biology (2018)

Raquel M. Melero-Fernandez de Mera Uma Thanigai Arasu Riikka Kärnä Sanna Oikari Kirsi Rilla

Hyaluronan synthase

10.1016/j.matbio.2018.10.004

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A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs

Nature Communications (2017)

Raquel M. Melero-Fernandez de Mera Lili Li Arkadiusz Popinigis Katryna Cisek Minna Tuittila

Engineering light-sensitive protein regulators has been a tremendous multidisciplinary challenge. Optogenetic regulators of MAPKs, central nodes of cellular regulation, have not previously been described. Here we present OptoJNKi, a light-regulated JNK inhibitor based on the AsLOV2 light-sensor domain using the ubiquitous FMN chromophore. OptoJNKi gene-transfer allows optogenetic applications, whereas protein delivery allows optopharmacology. Development of OptoJNKi suggests a design principle for other optically regulated inhibitors. From this, we generate Optop38i, which inhibits p38MAPK in intact illuminated cells. Neurons are known for interpreting temporally-encoded inputs via interplay between ion channels, membrane potential and intracellular calcium. However, the consequences of temporal variation of JNK-regulating trophic inputs, potentially resulting from synaptic activity and reversible cellular protrusions, on downstream targets are unknown. Using OptoJNKi, we reveal maximal regulation of c-Jun transactivation can occur at unexpectedly slow periodicities of inhibition depending on the inhibitor's subcellular location. This provides evidence for resonance in metazoan JNK-signalling circuits.

Photostimulation

10.1038/ncomms15017

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Unexpected Heterodivalent Recruitment of NOS1AP to nNOS Reveals Multiple Sites for Pharmacological Intervention in Neuronal Disease Models

Journal of Neuroscience (2015)

Lili Li Raquel M. Melero-Fernandez de Mera Jia Chen Wei Ba Nael Nadif Kasri

The protein NOS1AP/CAPON mediates signaling from a protein complex of NMDA receptor, PSD95 and nNOS. The only stroke trial for neuroprotectants that showed benefit to patients targeted this ternary complex. NOS1AP/nNOS interaction regulates small GTPases, iron transport, p38MAPK-linked excitotoxicity, and anxiety. Moreover, the nos1ap gene is linked to disorders from schizophrenia, post-traumatic stress disorder, and autism to cardiovascular disorders and breast cancer. Understanding protein interactions required for NOS1AP function, therefore, has broad implications for numerous diseases. Here we show that the interaction of NOS1AP with nNOS differs radically from the classical PDZ docking assumed to be responsible. The NOS1AP PDZ motif does not bind nNOS as measured by multiple methods. In contrast, full-length NOS1AP forms an unusually stable interaction with nNOS. We mapped the discrepancy between full-length and C-terminal PDZ motif to a novel internal region we call the ExF motif. The C-terminal PDZ motif, although neither sufficient nor necessary for binding, nevertheless promotes the stability of the complex. It therefore potentially affects signal transduction and suggests that functional interaction of nNOS with NOS1AP might be targetable at two distinct sites. We demonstrate that excitotoxic pathways can be regulated, in cortical neuron and organotypic hippocampal slice cultures from rat, either by the previously described PDZ ligand TAT-GESV or by the ExF motif-bearing region of NOS1AP, even when lacking the critical PDZ residues as long as the ExF motif is intact and not mutated. This previously unrecognized heterodivalent interaction of nNOS with NOS1AP may therefore provide distinct opportunities for pharmacological intervention in NOS1AP-dependent signaling and excitotoxicity.

PDZ domain

10.1523/jneurosci.0037-15.2015

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