@article{González-Avendaño2026,

title = {Computational Mapping and Targeting of BK Channel Protein–Protein Interactions in Breast Cancer},

author = {Mariela González-Avendaño and Roberto Rosales-Rojas and Ariela Vergara-Jaque },

doi = {10.1021/acs.jcim.6c00191},

year  = {2026},

date = {2026-03-17},

abstract = {Large-conductance Ca2+-activated potassium (BK) channels are widely expressed across human tissues and play fundamental roles in the regulation of diverse cellular processes. Dysregulation of BK channel expression or activity has been implicated in multiple pathological conditions, including cancer, where BK channel overexpression is associated with enhanced tumor cell proliferation and altered cellular dynamics. In this study, we present an integrative computational framework to identify, structurally characterize, and rationally target BK channel-associated protein–protein interactions (PPI) in breast cancer. RNA-seq differential expression analysis revealed significant overexpression of KCNMA1 in estrogen-sensitive breast cancer cells, supporting a central role for BK channels in tumor-associated phenotypes. By integrating transcriptomic data with curated interaction databases and PPI prediction methods, we constructed a breast cancer-specific interaction network centered on BK and identified ACTG2, LINGO1, and RAB4A as high-confidence interaction partners. Structural modeling and coarse-grained molecular dynamics simulations revealed stable, partner-specific interaction interfaces between BK and each interactor, identifying key residues governing complex formation. Building on these results, we present the first computational structural model of the BK-LINGO1 complex, which reveals a predominantly hydrophobic transmembrane interface consistent with the established role of LINGO1 as a regulatory accessory subunit. Leveraging this PPI interface, we designed peptide-based modulators using a structure-guided approach and identified peptide variants with enhanced conformational stability and favorable binding energetics. Overall, our work establishes a robust computational framework for mapping BK channel protein–protein interactions in breast cancer and demonstrates the feasibility of targeting these interactions through rational peptide design, opening new opportunities for the selective modulation of BK channel function in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Peña-Vilches2026,

title = {Identification of 14-3-3 Proteins as Binding Partners of TRP Channels},

author = {Nicolás Peña-Vilches and Mariela González-Avendaño and Nicole Soto-García and Diego Maureira and Ian Silva and Javiera Avilés and Elías Manríquez-Benítez and Exequiel Medina and Oscar Cerda and Pablo Galaz-Davison and Ariela Vergara-Jaque},

doi = {10.1021/acs.jcim.6c00092},

year  = {2026},

date = {2026-03-16},

abstract = {Transient receptor potential (TRP) channels are regulated by a diverse network of intracellular partners that govern their trafficking, stability, and functional expression at the plasma membrane. Here, we present a comprehensive and integrative characterization of 14-3-3 proteins as conserved binding partners of TRP channels. Leveraging the extensive structural repertoire of 14-3-3 complexes resolved to date, we combined large-scale sequence and structural analyses with molecular docking, coevolutionary inference, machine learning-based predictions, atomistic simulations, and targeted experimental validation to elucidate the molecular principles underlying TRP-14-3-3 recognition. Integration of these approaches into a unified consensus scoring framework revealed recurrent, solvent-exposed cytoplasmic motifs across the TRP channel family with a high propensity for 14-3-3 binding. Focusing on the TRPM4-14-3-3γ interaction, we identified an N-terminal cytoplasmic region of the channel as the primary 14-3-3 binding hotspot. Structural modeling and molecular dynamics simulations revealed a stable electrostatically driven interface, which was experimentally validated by fluorescence anisotropy assays. Moreover, biochemical and functional analyses demonstrated that TRPM4 interacts not only with 14-3-3γ but also with 14-3-3η, leading to a reduced channel-mediated sodium influx. Together, these findings establish 14-3-3 proteins as general and evolutionarily conserved regulators of TRP channels and provide a broadly applicable framework for identifying transient protein–protein interactions relevant to TRP channel dysregulation in disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Exploring a peripheral PIP2-binding site and its role in the alternative regulation of the TRP channel superfamily},

author = {L. Gonzalo Espinoza-Arcos and Mariela González-Avendaño and Matias Zuñiga-Bustos and Ricardo A. Zamora and Ariela Vergara-Jaque and Horacio Poblete},

doi = {10.1085/jgp.202413574},

year  = {2025},

date = {2025-11-03},

abstract = {Phosphatidylinositol 4,5-bisphosphate (PIP2) is recognized as an essential modulator of transient receptor potential (TRP) channels. Specifically, it influences the vanilloid receptor I (TRPV1), a pain receptor activated by a wide range of stimuli, including the binding of phospholipids, such as PIP2. The primary PIP2-binding site in TRPV1 has been identified through advanced techniques, revealing that the PIP2 binds to a specific pocket composed of positively charged residues located predominantly within the proximal C-terminus region. Additionally, a conserved segment with positively charged amino acids, K431 and R432, situated at the beginning of TRPV1's S1 transmembrane domain, has attracted considerable attention from the TRP research community. To date, our knowledge of this site's function and the subsequent effects following PIP2 binding is still emerging. In this work, MD simulations were conducted using coarse-grained models to investigate the binding dynamics of PIP2 on both WT and various mutated forms of TRPV1 channels. Our findings indicate that the K431A and R432A mutations significantly reduce the frequency of PIP2 contacts, suggesting that these mutated residues are part of a "peripheral binding pocket." This pocket seems to play a crucial role in facilitating the entry of PIP2 to the TRPV1 channel's primary binding site. Furthermore, our research has shown that these highly conserved residues within the TRPV subfamily are also structurally conserved across other TRP subfamilies, such as TRPM and TRPC, a detail not evident from sequence alignment alone. Consequently, we propose the existence of a structurally conserved peripheral PIP2-binding site shared among the diverse members of the TRP family, which can be categorized into distinct subfamilies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Structural basis of the inhibition of TRPV1 by analgesic sesquiterpenes},

author = {Mariela González-Avendaño and Raul Sanchez-Hernandez and Miguel Benítez-Angeles and Irina A. Talyzina and Itzel Llorente and Felix Sierra and Angelica Mendez-Resendiz and Francisco Mercado and Ariela Vergara-Jaque and Alexander I. Sobolevsky and León D. Islas and Tamara Rosenbaum},

doi = {10.1073/pnas.2506560122},

year  = {2025},

date = {2025-07-25},

urldate = {2025-07-25},

abstract = {The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in primary nociceptive afferents, which participate in processes such as pain and inflammation. Considerable efforts have been directed toward finding inhibitors of TRPV1 and understanding the molecular details of their interactions with this channel. α-humulene (AH) is a sesquiterpene derived from plants such as hops and other members of Cannabaceae family, with a long history of popular use as an analgesic and anti-inflammatory. Using a combination of behavioral assays, electrophysiology, site-directed mutagenesis, cryo-EM, and molecular dynamics simulations, we show that AH inhibits TRPV1-related pain responses and currents by interacting with a region composed of the S2, S2-S3 linker, and S3 transmembrane segments and stabilizing the closed conformation of the channel. The interaction of ligands in this region of the TRPV1 channel has not been previously described and the results of the present study highlight that it may constitute part of a negative regulatory region. These findings allow us to understand the molecular basis by which substances such as some sesquiterpenes, abundantly found in medicinal plants used by humans for hundreds of years, reduce pain. Pain management can include the use of opioids, which results in hepatic and renal damage and possible addiction. Our study offers insight into a poorly understood group of compounds that could be used as scaffold to produce novel nonopioid analgesic therapies and clarifies the molecular mechanisms that underlie the effects of these analgesic molecules.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{González-Avendaño2025,

title = {Rhotekin-1 is a novel interacting protein and regulator of TRPC6 activity},

author = {Mariela González-Avendaño and Boris Lavanderos and Octavio Orellana-Serradelll and Diego Maureira and Pablo Cruz and Ian Silva and Jorge Toledo and Joaquín López and Rodrigo Santos and Felipe Arancibia and Diego Varela and Mónica Cáceres and Ariela Vergara-Jaque and Oscar Cerda },

doi = {10.1111/febs.70028},

year  = {2025},

date = {2025-03-02},

urldate = {2025-03-02},

abstract = {Dysregulation of Transient Receptor Potential Canonical 6 (TRPC6) channel is associated with pathologies in which cell contraction is relevant. Therefore, understanding the molecular mechanisms underlying the regulation of actin cytoskeletal function by TRPC6 is important. Here, we observed that TRPC6 upregulates the activity of RhoA GTPase, affecting the organization and polymerization of the actin cytoskeleton and focal adhesion dynamics. Moreover, TRPC6 activity promoted cell contraction and migration. Using mass spectrometry, we identified Rhotekin-1 (RTKN-1), an effector of RhoA, as a new TRPC6-interacting protein. In addition, RTKN-1 expression prevented the effects of TRPC6 on cell contraction, migration, and spreading. Moreover, calcium imaging, TRPC6-jGCaMP8f recordings, and patch clamp assays showed that RTKN-1 acts as a negative regulator of TRPC6 activity by reducing the abundance of TRPC6 in the plasma membrane through a mechanism that depends on RhoA activation. In this context, we found that RTKN-1 expression increased the endocytosis of TRPC6 in the early endosome compartment. In summary, these results suggest RTKN-1 as a new interactor and regulator of TRPC6 activity through a novel mechanism involving the modulation of TRPC6 trafficking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{González-Avendaño2024b,

title = {The power of computational proteomics platforms to decipher protein-protein interactions},

author = {Mariela González-Avendaño and Joaquín López and Ariela Vergara-Jaque and Oscar Cerda},

doi = {10.1016/j.sbi.2024.102882},

issn = {0959-440X},

year  = {2024},

date = {2024-10-00},

journal = {Current Opinion in Structural Biology},

volume = {88},

publisher = {Elsevier BV},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bravo-Moraga2024,

title = {Understanding the Differences of Danusertib’s Residence Time in Aurora Kinases A/B: Dissociation Paths and Key Residues Identified using Conventional and Enhanced Molecular Dynamics Simulations},

author = {Felipe Bravo-Moraga and Mauricio Bedoya and Ariela Vergara-Jaque and Jans Alzate-Morales},

doi = {10.1021/acs.jcim.4c00387},

issn = {1549-960X},

year  = {2024},

date = {2024-06-24},

journal = {J. Chem. Inf. Model.},

volume = {64},

number = {12},

pages = {4759--4772},

publisher = {American Chemical Society (ACS)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Peña-Varas2022,

title = {Structural Insights into the Substrate Transport Mechanisms in GTR Transporters through Ensemble Docking},

author = {Carlos Peña-Varas and Christa Kanstrup and Ariela Vergara-Jaque and Mariela González-Avendaño and Christoph Crocoll and Osman Mirza and Ingo Dreyer and Hussam Nour-Eldin and David Ramírez},

doi = {10.3390/ijms23031595},

year  = {2022},

date = {2022-01-28},

urldate = {2022-01-28},

abstract = {Glucosinolate transporters (GTRs) are part of the nitrate/peptide transporter (NPF) family, members of which also transport specialized secondary metabolites as substrates. Glucosinolates are defense compounds derived from amino acids. We selected 4-methylthiobutyl (4MTB) and indol-3-ylmethyl (I3M) glucosinolates to study how GTR1 from Arabidopsis thaliana transports these substrates in computational simulation approaches. The designed pipeline reported here includes massive docking of 4MTB and I3M in an ensemble of GTR1 conformations (in both inward and outward conformations) extracted from molecular dynamics simulations, followed by clustered and substrate–protein interactions profiling. The identified key residues were mutated, and their role in substrate transport was tested. We were able to identify key residues that integrate a major binding site of these substrates, which is critical for transport activity. In silico approaches employed here represent a breakthrough in the plant transportomics field, as the identification of key residues usually takes a long time if performed from a purely wet-lab experimental perspective. The inclusion of structural bioinformatics in the analyses of plant transporters significantly speeds up the knowledge-gaining process and optimizes valuable time and resources.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Rossino2021,

title = {Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization},

author = {Giacomo Rossino and Marta Rui and Pasquale Linciano and Daniela Rossi and Massimo Boiocchi and Marco Peviani and Elena Poggio and Daniela Curti and Dirk Schepmann and Bernhard Wunsch and Mariela González-Avendaño and Ariela Vergara-Jaque and Julio Caballero and Simona Collina},

doi = {10.1021/acs.jmedchem.1c00886},

year  = {2021},

date = {2021-10-08},

urldate = {2021-10-08},

abstract = {The sigma 1 receptor (S1R) is an enigmatic ligand-operated chaperone involved in many important biological processes, and its functions are not fully understood yet. Herein, we developed a novel series of bitopic S1R ligands as versatile tools to investigate binding processes, allosteric modulation, and the oligomerization mechanism. These molecules have been prepared in the enantiopure form and subjected to a preliminary biological evaluation, while in silico investigations helped to rationalize the results. Compound 7 emerged as the first bitopic S1R ligand endowed with low nanomolar affinity (Ki = 2.6 nM) reported thus far. Computational analyses suggested that 7 may stabilize the open conformation of the S1R by simultaneously binding the occluded primary binding site and a peripheral site on the cytosol-exposed surface. These findings pave the way to new S1R ligands with enhanced activity and/or selectivity, which could also be used as probes for the identification of a potential allosteric site.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{González-Avendaño2021,

title = {PPI-MASS: An Interactive Web Server to Identify Protein-Protein Interactions From Mass Spectrometry-Based Proteomics Data},

author = {Mariela González-Avendaño and Simon Zuñiga-Almonacid and Ian Silva and Boris Lavanderos and Felipe Robinson and Roberto Rosales-Rojas and Fabio Durán-Verdugo and Wendy González and Mónica Cáceres and Oscar Cerda and Ariela Vergara-Jaque},

doi = {10.3389/fmolb.2021.701477},

year  = {2021},

date = {2021-06-30},

urldate = {2021-06-30},

abstract = {Mass spectrometry-based proteomics methods are widely used to identify and quantify protein complexes involved in diverse biological processes. Specifically, tandem mass spectrometry methods represent an accurate and sensitive strategy for identifying protein-protein interactions. However, most of these approaches provide only lists of peptide fragments associated with a target protein, without performing further analyses to discriminate physical or functional protein-protein interactions. Here, we present the PPI-MASS web server, which provides an interactive analytics platform to identify protein-protein interactions with pharmacological potential by filtering a large protein set according to different biological features. Starting from a list of proteins detected by MS-based methods, PPI-MASS integrates an automatized pipeline to obtain information of each protein from freely accessible databases. The collected data include protein sequence, functional and structural properties, associated pathologies and drugs, as well as location and expression in human tissues. Based on this information, users can manipulate different filters in the web platform to identify candidate proteins to establish physical contacts with a target protein. Thus, our server offers a simple but powerful tool to detect novel protein-protein interactions, avoiding tedious and time-consuming data postprocessing. To test the web server, we employed the interactome of the TRPM4 and TMPRSS11a proteins as a use case. From these data, protein-protein interactions were identified, which have been validated through biochemical and bioinformatic studies. Accordingly, our web platform provides a comprehensive and complementary tool for identifying protein-protein complexes assisting the future design of associated therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}