Maggiore, F. | bioRxiv Science

bioRxiv2024

Molecular mechanism of thyroxine transport by monocarboxylate transporters

Thyroid hormones (the common name for prohormone thyroxine and the bioactive form triiodothyronine) control major developmental and metabolic processes. Release of thyroid hormones from the thyroid gland into the bloodstream and their transport into target cells is facilitated by plasma membrane transporters, of which monocarboxylate transporter (MCT)8 and the highly homologous MCT10 are most important. Patients with MCT8 mutations suffer from a severe neurodevelopmental and metabolic disorder, however, the molecular mechanism underlying thyroid hormone transport is unknown. Using cryogenic-sample electron microscopy (cryo-EM), we determined the ligand-free and thyroxine-bound human MCT8 structures in the outward-open state and the thyroxine-bound human MCT10 in the inward-facing state. Our structural analysis revealed a network of conserved gate residues involved in conformational changes upon thyroxine binding, triggering ligand release on the opposite compartment. We then determined the structure of a folded, but inactive patient-derived MCT8 mutant, indicating a subtle conformational change which explains its reduced transport activity. In addition, we determined the structure of MCT8 bound to its inhibitor silychristin, revealing an interaction with residues essential to drive transition to the inward-facing state, thereby locking the protein in the outward-facing state. This study provides molecular and structural insights into normal and disordered thyroid hormone transport.

biochemistry↗

bioRxiv2021

Active inference through whiskers

Rodents use whisking to probe actively their environment and to locate objects in space, hence providing a paradigmatic biological example of active sensing. Numerous studies show that the control of whisking has anticipatory aspects. For example, rodents target their whisker protraction to the distance at which they expect objects, rather than just reacting fast to contacts with unexpected objects. Here we characterize the anticipatory control of whisking in rodents as an active inference process. In this perspective, the rodent is endowed with a prior belief that it will touch something at the end of the whisker protraction, and it continuously modulates its whisking amplitude to minimize (proprioceptive and somatosensory) prediction errors arising from an unexpected whisker-object contact, or from a lack of an expected contact. We will use the model to qualitatively reproduce key empirical findings about the ways rodents modulate their whisker amplitude during exploration and the scanning of (expected or unexpected) objects. Furthermore, we will discuss how the components of active inference model can in principle map to the neurobiological circuits of rodent whisking.

animal behavior and cognition↗