Luis Valencia

All Publications

• FCHo2, not talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions. Nature communications Lu, C. H., Lee, C. E., Zhang, W., Yang, Y., Valencia, L. A., You, H., Tsai, C. T., Cui, B. 2026

  Abstract

  Extensive studies have shown that talin is the essential player for inside-out activation of integrins by binding to the intracellular tail of β integrins. Here we show that, while talin binding is essential for inside-out integrin activation in focal adhesions, it is dispensable in curved adhesions - a distinct adhesion architecture exclusively mediated by integrin αvβ5 and selectively formed at curved membranes. Instead, a curvature-sensing protein FCHo2 binds to the HDRRE motif in integrin β5's cytoplasmic tail and inside-out activates integrin αvβ5 in curved adhesions. FCHo2 does not bind to a similar motif in the homologous integrin β3. We identify a pivotal tryptophan (W), which is conserved in all homologous β integrins except β5, where it is replaced by a tyrosine (Y766). This tyrosine substitution is crucial for integrin β5's unique capability in forming curved adhesions. Furthermore, our studies suggest that the phosphorylation state of Y766 regulates whether integrin ɑvβ5 forms curved adhesions or focal adhesions. Overall, our work unveils distinct molecular interactions and regulatory mechanisms between curved adhesions and focal adhesions.

  View details for DOI 10.1038/s41467-026-68942-y

  View details for PubMedID 41651837

• Membrane curvature at the ER-PM contact sites. Trends in cell biology Yang, Y., Valencia, L. A., Cui, B. 2025

  Abstract

  Membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) are essential for lipid transfer, calcium signaling, and membrane organization. While the formation and function of ER-PM contacts are increasingly well-characterized, the spatiotemporal regulation of their localization remains elusive. Emerging evidence using nanopatterned substrates, ultrastructural imaging, and protein localization analyses indicates that membrane curvature can act as a spatial cue for the recruitment of specific tethering proteins, influencing where contact sites form. This opinion article synthesizes recent advances linking membrane topography ER-PM contact organization and highlights systems where curvature actively orchestrates contact position through curvature-sensing proteins. It also outlines key unanswered questions about how membrane curvature integrates into broader signaling networks that govern organelle contact communication.

  View details for DOI 10.1016/j.tcb.2025.10.002

  View details for PubMedID 41203510

• Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum. Nature cell biology Yang, Y., Valencia, L. A., Lu, C. H., Nakamoto, M. L., Tsai, C. T., Liu, C., Yang, H., Zhang, W., Jahed, Z., Lee, W. R., Santoro, F., Liou, J., Wu, J. C., Cui, B. 2024

  Abstract

  Contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules, we hypothesize that PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, whereas the ubiquitously expressed extended synaptotagmin-2 does not show a preference for PM curvature. At the mechanistic level, we find that the low-complexity region (LCR) and membrane occupation and recognition nexus (MORN) motifs of junctophilins can bind independently to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins-Eps15 homology domain-containing proteins-that interact with the MORN_LCR motifs and facilitate the preferential tethering of junctophilins to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

  View details for DOI 10.1038/s41556-024-01511-x

  View details for PubMedID 39289582

  View details for PubMedCentralID 6427007

• The AMIGO1 adhesion protein activates Kv2.1 voltage sensors. Biophysical journal Sepela, R. J., Stewart, R. G., Valencia, L. A., Thapa, P., Wang, Z., Cohen, B. E., Sack, J. T. 2022

  Abstract

  Kv2 voltage-gated potassium channels are modulated by amphoterin-induced gene and open reading frame (AMIGO) neuronal adhesion proteins. Here, we identify steps in the conductance activation pathway of Kv2.1 channels that are modulated by AMIGO1 using voltage-clamp recordings and spectroscopy of heterologously expressed Kv2.1 and AMIGO1 in mammalian cell lines. AMIGO1 speeds early voltage-sensor movements and shifts the gating charge-voltage relationship to more negative voltages. The gating charge-voltage relationship indicates that AMIGO1 exerts a larger energetic effect on voltage-sensor movement than is apparent from the midpoint of the conductance-voltage relationship. When voltage sensors are detained at rest by voltage-sensor toxins, AMIGO1 has a greater impact on the conductance-voltage relationship. Fluorescence measurements from voltage-sensor toxins bound to Kv2.1 indicate that with AMIGO1, the voltage sensors enter their earliest resting conformation, yet this conformation is less stable upon voltage stimulation. We conclude that AMIGO1 modulates the Kv2.1 conductance activation pathway by destabilizing the earliest resting state of the voltage sensors.

  View details for DOI 10.1016/j.bpj.2022.03.020

  View details for PubMedID 35314141