Research interests // Selected publications
Research interests
We study signal transduction processes at molecular level that may
yield to biomedical and biotechnological applications. Calcium ion
(Ca2+) is a key signal in multiple biological
phenomena ranging from
neurotransmission to gene expression. Changes in the concentration of
intracellular free Ca2+ ([Ca2+]i,
their location, amplitude and
duration, are essential to transmit information through the nervous
system. The mechanisms by which these changes can bring about such
diverse responses rely on the ability of Ca2+
sensors to decode Ca2+
signals. Neurons contain four types of very specialized Ca2+
sensors:
synaptotagmins, C2 domain containing proteins that control fast
neurotransmitter release, the ubiquitous EF-hand containing sensor
Calmodulin, and two neuronal EF-hand containing families of proteins,
the Calneurons and the Neuronal Calcium Sensors (NCSs).
We focus our research on the Neuronal Calcium Sensor 1 (NCS-1), the
most abundant protein of the NCS family. NCS-1 is implicated in a wide
range of important neuronal functions such as neurite outgrowth,
synaptic plasticity, neuroprotection and axonal regeneration, thus
having an impact in learning and memory processes. Furthermore, NCS-1
has been related to several mental disorders (X-linked mental
retardation, autism, schizophrenia or bipolar disorder) and cancer. For
all these reasons, NCS-1 is an attractive therapeutic target.
To perform its functions, NCS-1 interacts and regulate the activity of
several unrelated target proteins such as ion channels, G protein
coupled receptors, guanine exchange factors and kinases, establishing
cross-talk with other signaling pathways. Our group is interested is in
understanding at atomic level how NCS-1 interacts with its target
proteins and the implication of specific pathways in normal neuronal
function and disease. In doing so, we aim to find out new compounds
able to regulate NCS-1 mediated protein-protein interactions with
therapeutic potential.
In order to achieve our goals, we carry out a multidisciplinary
approach using strategies of Structural, Biochemical, Biophysical,
Molecular and Chemical Biology. The structure solution of proteins at
atomic level by X-ray crystallography and the analysis of
protein-protein, protein-membrane or protein-small molecules
interactions are the starting point of our projects. The structural
studies are essential to understand the molecular mechanisms of action
of the proteins and to perform a drug discovery structure-based
approach to find new protein-protein interaction modulators. We further
corroborate our hypothesis by using a whole range of biophysical,
biochemical, molecular and cellular biological techniques. We have
stablished a strong collaboration with Dr.
Nuria Campillo (ICMAT, CSIC)
and Dr.
Alicia Mansilla (IRYCIS-UAH), to combine our experimental
structural data with computational studies and finally test the
potential hit compounds in vivo. More recently, we have established
collaborations with Prof.
Stephen R Sprang (U. Montana, USA), to study
G-protein nucleotide exchange, and Dr.
Javier
García-Nafría (BIFI, Zaragoza) to
combine
crystallographic data with cryo-electron microscopy.
Selected
publications
The neuronal calcium
sensor NCS-1 regulates the phosphorylation state and activity of the
Gα
chaperone and GEF Ric-8A
Daniel Muñoz-Reyes, Levi J McClelland, Sandra Arroyo-Urea,
Sonia
Sánchez-Yepes, Juan Sabín, Sara
Pérez-Suárez, Margarita Menendez, Alicia
Mansilla, Javier
García-Nafría, Stephen Sprang, Maria
José
Sánchez-Barrena*
eLife (2023) 12:e86151
(doi: 10.7554/eLife.86151)
(see
also this picture)
bioRxiv (2022) 12.09.519724 (doi: 10.1101/2022.12.09.519724)
The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome
mice model phenotypes
Cogram P, Fernández-Beltrán LC, Casarejos MJ,
Sánchez-Yepes S, Rodríguez-Martín E,
García-Rubia A, Sánchez-Barrena MJ, Gil C,
Martínez A, Mansilla A*
Frontiers in Neuroscience (2022)
16, 1007531 (doi:
10.3389/fnins.2022.1007531)
Insights into real-time chemical processes in a calcium sensor
protein-directed dynamic library. Canal-Martín A, Sastre J,
Sanchez-Barrena MJ*, Canales A, Baldominos S, Pascual N,
Martínez-González L, Molero D,
Fernández-Valle ME, Sáez E, Blanco-Gabella P,
Gómez-Rubio E, Martín-Santamaría S,
Sáiz A, Mansilla A*, Cañada FJ,
Jiménez-Barbero J, Martínez A,
Pérez-Fernández R*
Nature Communications (2019) 10,
Art. No. 2798 (doi:
10.1038/s41467-019-10627-w)
Deciphering the inhibition of the neuronal calcium sensor 1 and the
guanine exchange factor Ric8a with a small phenothiazine molecule for
the rational generation of therapeutic synapse function regulators
Roca C, Martínez-González L, Daniel-Mozo M,
Sastre J, Infantes L, Mansilla A, Chaves-Sanjuán A,
González-Rubio JM, Gil C, Cañada J,
Martínez A, Sánchez-Barrena MJ*, Campillo NE*
Journal of Medicinal Chemistry
(2018) 61(14), 5910-5921 (doi:10.1021/acs.jmedchem.8b00088)
Interference of the complex between NCS-1 and Ric8a with phenothiazines
regulates synaptic function and is an approach for fragile X syndrome
Mansilla A, Chaves-Sanjuán A, Campillo NE, Semelidou O,
Martínez-González L, Infantes L,
González-Rubio JM, Gil C, Conde S, Skoulakis E,
Ferrús A, Martínez A, Sánchez-Barrena
MJ*
Proceedings PNAS (2017) 114,
E999–E1008 (doi:10.1073/pnas.1611089114)
The guanine-exchange factor Ric8a binds the calcium sensor NCS-1 to
regulate synapse number and probability of release
Romero-Pozuelo J, Dason JS, Mansilla A, Baños-Mateos S,
Sardina JL, Chaves-Sanjuán A, Jurado-Gómez J,
Santana E, Atwood HL, Hernández-Hernández A,
Sánchez-Barrena MJ, Ferrús A
Journal of Cell Science (2014)
127, 4246-4259 (doi:10.1242/jcs.152603)
