Biology subjects

Araya-Secchi, R.

Publications and source records attributed to Araya-Secchi, R..

9 recordsLinked to original sources

bioRxiv2026

A historical cross-border Andes virus lineage reveals the origin of a cruise ship hantavirus pulmonary syndrome outbreak

Andes virus (ANDV) caused a multi-country outbreak of hantavirus pulmonary syndrome among passengers and crew of a cruise ship in 2026. To investigate the origin and evolutionary history of the virus responsible for the outbreak, we analyzed complete ANDV small (S), medium (M), and large (L) genome segment sequences from Chile alongside outbreak-associated and publicly available genome sequences. Across all three segment-specific phylogenies, the outbreak virus clustered within an ANDV Clade III cluster spanning southern Chile and northern Patagonia in Argentina and were most closely related to a human-derived ANDV (p1236) collected in Los Rios Region of Chile in 2012, representing the closest known historical relative of the outbreak-associated virus. Phylogeographic analysis showed that the genetically distinct ANDV Clade V lineage circulating in central Chile was not closely related to the cruise ship outbreak-associated genomes, thereby reducing the likelihood that the index cases acquired infection through zoonotic spillover while traveling through the Maule Region. These findings trace the geographic origin of the outbreak-associated virus to a defined corridor, the Hua Hum Pass, a cross-border zone connecting Province of Neuquen in Argentina with the Los Rios and La Araucania Regions of Chile.

evolutionary biology↗

bioRxiv2025

Tracing the evolution of prestin's area-motor activity through ancestral sequence reconstruction and structural modeling

Prestin, a member of the SLC26A family, is essential for the electromotility of mammalian outer hair cells, converting voltage changes into mechanical work. In contrast, nonmammalian orthologues function as anion transporters. To investigate the molecular and structural basis of this functional divergence, we performed ancestral sequence reconstruction (ASR) of prestin across vertebrates, followed by structural modeling using AlphaFold2-multimer and molecular dynamics simulations. We identified more than 200 amino acid substitutions along the lineage that lead to placental mammals, with early substitutions concentrated in the transmembrane domain (TMD) and late substitutions clustering in the STAS domain, particularly in the intervening sequence (IVS). Structural modeling and simulation revealed that early substitutions modulate protein-lipid interactions and interhelical contacts. In placental mammals, the IVS-loop adopts a distinct conformation that places a negatively charged patch near the chloride access pathway, potentially affecting the ion dynamics and voltage responsiveness. These structural transitions occurred without major rearrangements of the global fold of prestin, supporting a notion in which the novel function evolved through distributed substitutions within a conserved scaffold. Our findings illustrate how molecular exaptation, and incremental structural remodeling enabled the repurposing of an ancestral anion transporter into a voltage-sensitive area-motor, providing a framework for understanding the molecular evolution of complex biophysical traits central to auditory neuroscience.

evolutionary biology↗

bioRxiv2025

Zebrafish armc9 mutant reveals a link between ARM-Type fold domain loss, inflammation, and spinal curvature

The vertebral column (VC) defines the central axis of vertebrates. Among its malformations, adolescent idiopathic scoliosis (AIS) is the most common, characterized by lateral spine curvature without congenital abnormalities. While its etiology remains elusive, genetic studies in zebrafish have linked AIS to skeletogenesis, cilia structure, cerebrospinal fluid flow, and inflammation. In this study, we characterized the zebrafish armc9 mutant, exhibiting AIS-like curvature without vertebral malformations, subcommissural organ, or Reissner fiber structure disruptions. We also detected an inflammatory response at the curvature origin. Structural bioinformatics and molecular docking analyses suggest that the mutant Armc9 protein partially lacks the functional ARM-type fold domain, which is crucial for its interaction with Togaram1, revealing that both proteins are relevant for ciliary signaling and spine curvature. Phylogenetic analyses indicate that the ARMC gene family encompasses 12 members, highlighting that the Armc9 gene has deep evolutionary roots. Our results demonstrate that the zebrafish armc9 mutant accurately represents the AIS phenotype, suggesting that the loss of Armc9s C-terminal ARM-type fold domain could affect the ciliary integrity and contribute to spine curvature by altering the skeletogenic environment. Taken together, this study proposes that the zebrafish armc9 mutant offers a unique opportunity to understand the etiology of AIS and provides new insights into the molecular interaction networks of Armc9 in ciliary signaling.

developmental biology↗

bioRxiv2022

The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate

Class 1 cytokine receptors transmit signals through the membrane by a single transmembrane helix to an intrinsically disordered cytoplasmic domain that lacks kinase activity. While specific binding to phosphoinositides has been reported for the prolactin receptor (PRLR), the role of lipids in PRLR signalling is unclear. Using an integrative approach combining NMR spectroscopy, cellular signalling experiments, computational modelling and simulation, we demonstrate co-structure formation of the disordered intracellular domain of the human PRLR, the membrane constituent phosphoinositide-4,5-bisphosphate (PI(4,5)P2) and the FERM-SH2 domain of the Janus kinase 2 (JAK2). We find that the complex leads to accumulation of PI(4,5)P2 at the transmembrane helix interface and that mutation of residues identified to interact specifically with PI(4,5)P2 negatively affects PRLR-mediated activation of signal transducer and activator of transcription 5 (STAT5). Facilitated by co-structure formation, the membrane-proximal disordered region arranges into an extended structure. We suggest that the co-structure formed between PRLR, JAK2 and PI(4,5)P2 locks the juxtamembrane disordered domain of the PRLR in an extended structure, enabling signal relay from the extracellular to the intracellular domain upon ligand binding. We find that the co-structure exists in different states which we speculate could be relevant for turning signalling on and off. Similar co-structures may be relevant for other non-receptor tyrosine kinases and their receptors.

biophysics↗

bioRxiv2021

Elastic versus Brittle Mechanical Responses Predicted for Dimeric Cadherin Complexes

Cadherins are a superfamily of adhesion proteins involved in a variety of biological processes that include the formation of intercellular contacts, the maintenance of tissue integrity, and the development of neuronal circuits. These transmembrane proteins are characterized by ectodomains composed of a variable number of extracellular cadherin (EC) repeats that are similar but not identical in sequence and fold. E-cadherin, along with desmoglein and desmocollin proteins, are three classical-type cadherins that have slightly curved ectodomains and engage in homophilic and heterophilic interactions through an exchange of conserved tryptophan residues in their N-terminal EC1 repeat. In contrast, clustered protocadherins are straighter than classical cadherins and interact through an antiparallel homophilic binding interface that involves overlapped EC1 to EC4 repeats. Here we present molecular dynamics simulations that model the adhesive domains of these cadherins using available crystal structures, with systems encompassing up to 2.8 million atoms. Simulations of complete classical cadherin ectodomain dimers predict a two-phased elastic response to force in which these complexes first softly unbend and then stiffen to unbind without unfolding. Simulated , {beta}, and {gamma} clustered protocadherin homodimers lack a two-phased elastic response, are brittle and stiffer than classical cadherins, and exhibit complex unbinding pathways that in some cases involve transient intermediates. We propose that these distinct mechanical responses are important for function, with classical cadherin ectodomains acting as molecular shock absorbers and with stiffer clustered protocadherin ectodomains facilitating overlap that favors binding specificity over mechanical resilience. Overall, our simulations provide insights into the molecular mechanics of single cadherin dimers relevant in the formation of cellular junctions essential for tissue function. Statement of SignificanceMulticellular organisms rely on cellular adhesion to survive, and this adhesion is mediated by diverse sets of proteins that include cadherins responsible for organ assembly and tissue integrity maintenance. As parts of cell-cell junctions in epithelial and cardiac tissues, classical cadherins experience forces and must be mechanically robust. In contrast, clustered protocadherins are responsible for neuronal connectivity and are exposed to more subtle mechanical stimuli. We used simulations to study the mechanics of isolated cadherin complexes and found that classical cadherins exhibit a two-phased elastic response that might prevent loss of adhesion during mild mechanical stress. Conversely, we predict that clustered protocadherin complexes are brittle. Our results suggest that each set of cadherins has evolved to adopt distinct mechanical properties.

biophysics↗

bioRxiv2021

Collective Mechanical Responses of Cadherin-Based Adhesive Junctions as Predicted by Simulations

Cadherin-based adherens junctions and desmosomes help stabilize cell-cell contacts with additional function in mechano-signaling, while clustered protocadherin junctions are responsible for directing neuronal circuits assembly. Structural models for adherens junctions formed by epithelial cadherin (CDH1) proteins indicate that their long, curved ectodomains arrange to form a periodic, two-dimensional lattice stabilized by tip-to-tip trans interactions (across junction) and lateral cis contacts. Less is known about the exact architecture of desmosomes, but desmoglein (DSG) and desmocollin (DSC) cadherin proteins are also thought to form ordered junctions. In contrast, clustered protocadherin (PCDH) based cell-cell contacts in neuronal tissues are thought to be responsible for self-recognition and avoidance, and structural models for clustered PCDH junctions show a linear arrangement in which their long and straight ectodomains form antiparallel overlapped trans complexes. Here we report all-atom molecular dynamics simulations testing the mechanics of minimalistic adhesive junctions formed by CDH1, DSG2 coupled to DSC1, and PCDH{gamma}B4, with systems encompassing up to 3.7 million atoms. Simulations generally predict a favored shearing pathway for the adherens junction model and a two-phased elastic response to tensile forces for the adhesive adherens junction and the desmosome models. Complexes within these junctions first unbend at low tensile force and then become stiff to unbind without unfolding. However, cis interactions in both the CDH1 and DSG2-DSC1 systems dictate varied mechanical responses of individual dimers within the junctions. Conversely, the clustered protocadherin PCDH{gamma}B4 junction lacks a distinct two-phased elastic response. Instead, applied tensile force strains trans interactions directly as there is little unbending of monomers within the junction. Transient intermediates, influenced by new cis interactions, are observed after the main rupture event. We suggest that these collective, complex mechanical responses mediated by cis contacts facilitate distinct functions in robust cell-cell adhesion for classical cadherins and in self-avoidance signaling for clustered PCDHs. Statement of SignificanceProteins that mediate cell-cell contacts often form aggregates in vivo where the tight packing of monomers into junctions is relevant to their function. Members of the cadherin superfamily of glycoproteins form large complexes in which their long ectodomains interact to mediate cell-cell adhesion. Here, we employ simulations to elucidate complex mechanical responses of five junction systems in response to force. Our results offer atomistic insights into the behavior of these proteins in a crowded physiological context, suggesting that classical cadherin complexes in adherens junctions and desmosomes act as molecular shock absorbers with responses modulated by dynamic lateral contacts, while clustered protocadherins form brittle junctions that upon stretching and unbinding form transient interfaces suitable for their critical role in neuronal self-recognition.

biophysics↗

bioRxiv2020

Order and disorder - an integrative structure of the full-length human growth hormone receptor

Despite the many physiological and pathophysiological functions of the human growth hormone receptor (hGHR), a detailed understanding of its modus operandi is hindered by the lack of structural information of the entire receptor at the molecular level. Due to its relatively small size (70 kDa) and large content of structural disorder (>50%), this membrane protein falls between the cracks of conventional high-resolution structural biology methods. Here, we study the structure of the full-length hGHR in nanodiscs with small angle-X-ray scattering (SAXS) as the foundation. We developed an approach in which we combined SAXS, X-ray diffraction and NMR spectroscopy obtained on the individual domains and integrated the data through molecular dynamics simulations to interpret SAXS data on the full-length hGHR in nanodiscs. The structure of the hGHR was determined in its monomeric state and provides the first experimental model of any full-length cytokine receptor in a lipid membrane. Combined, our results highlight that the three domains of the hGHR are free to reorient relative to each other, resulting in a broad structural ensemble. Our work exemplifies how integrating experimental data from several techniques computationally, may enable the characterization of otherwise inaccessible structures of membrane proteins with long disordered regions, a widespread phenomenon in biology. To understand orchestration of cellular signaling by disordered chains, the hGHR is archetypal and its structure emphasizes that we need to take a much broader, ensemble view on signaling.

biophysics↗

bioRxiv2019

Structural determinants of protocadherin-15 elasticity and function in inner-ear mechanotransduction

Protocadherin-15 (PCDH15), an atypical member of the cadherin superfamily, is essential for vertebrate hearing and its dysfunction has been associated with deafness and progressive blindness. The PCDH15 ectodomain, made of eleven extracellular cadherin (EC1-11) repeats and a membrane adjacent domain (MAD12), assembles as a parallel homodimer that interacts with cadherin-23 (CDH23) to form the tip link, a fine filament necessary for inner-ear mechanotransduction. Here we report X-ray crystal structures of a PCDH15 + CDH23 heterotetrameric complex and ten PCDH15 fragments that were used to build complete high-resolution models of the monomeric PCDH15 ectodomain. Using molecular dynamics (MD) simulations and validated crystal contacts we propose models for complete PCDH15 parallel homodimers and the tip-link bond. Steered MD simulations of these models predict their strength and suggest conditions in which a multimodal PCDH15 ectodomain can act as a stiff or soft gating spring. These results provide a detailed view of the first molecular steps in inner-ear sensory transduction.

biophysics↗

bioRxiv2018

A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15

The cadherin superfamily of proteins is defined by the presence of extracellular cadherin (EC) repeats that engage in protein-protein interactions to mediate cell-cell adhesion, cell signaling, and mechanotransduction. The extracellular domains of non-classical cadherins often have a large number of EC repeats along with other subdomains of various folds. Protocadherin-15 (PCDH15), a protein component of the inner-ear tip link filament essential for mechanotransduction, has eleven EC repeats and a membrane adjacent domain (MAD12) of atypical fold. Here we report the crystal structure of a pig PCDH15 fragment including EC10, EC11, and MAD12 in a parallel dimeric arrangement. MAD12 has a unique molecular architecture and folds as a ferredoxin-like domain similar to that found in the nucleoporin protein Nup54. Analytical ultracentrifugation experiments along with size exclusion chromatography coupled to multi-angle laser light scattering and small-angle X-ray scattering corroborate the crystallographic dimer and show that MAD12 induces parallel dimerization of PCDH15 near its membrane insertion point. In addition, steered molecular dynamics simulations suggest that MAD12 is mechanically weak and may unfold before tip-link rupture. Sequence analyses and structural modeling predict the existence of similar domains in cadherin-23, protocadherin-24, and the \"giant\" FAT and CELSR cadherins, indicating that some of them may also exhibit MAD-induced parallel dimerization.

biophysics↗