Study reveals how a key hearing protein functions, shedding light on how genetic mutations can cause progressive hearing loss.
At a seminar held on February 27th in São Paulo, researcher Nicolas Wolff, from the Institut Pasteur (Paris), presented new insights on the molecular mechanisms underlying hearing – and the mutations associated with deafness and Usher syndrome. As a specialist in integrated structural biology, Wolff has demonstrated that combining high-resolution methodologies — such as Cryo-EM, NMR, X-ray crystallography, super-resolution microscopy (STED), and cryo-electron tomography — enables detailed nanometric-scale analysis of the structure of protein complexes crucial for hair cell formation and essential for converting sound into electrical signals.
Atomic structure and genetic diseases
Hair cells are located inside the cochlea — a spiral-shaped structure in the inner ear, and play a crucial role in hearing. They function as microscopic sensors, capturing sound vibrations and transforming them into electrical signals that the brain interprets as sound. This process relies on extremely delicate connections between small projections of these cells, called stereocilia. If these connections fail, sound transmission breaks down — leading to different forms of deafness.
During the lecture, Wolff shared new findings about a group of proteins involved in creating microscopic connections called ankle links. This structure acts as a kind of “support bridge” between the stereocilia as hair cells are developing, helping them acquire the correct shape and mechanical configuration required for their functioning.
When this molecular mechanism does not organize itself as it should, the consequences can be serious. Changes in proteins that make up this complex — such as ADGRV1 (also called VLGR1), whirlin, and PDZD7 — are associated with Usher syndrome type 2, a genetic condition characterized by congenital deafness and progressive vision loss.
By 2050, over 2.5 billion people worldwide are expected to experience hearing loss, with genetics being a major cause in many cases. According to Wolff, over 100 genes have been associated with sensorineural hearing loss, caused by damage to the sensory cells of the cochlea or the auditory nerve.
Structural biology plays a vital role here. By examining how proteins assemble, interact, and maintain their stability at the molecular level, we can determine how specific mutations disrupt this balance. This approach shifts the analysis from the clinical scale to the atomic scale — where small structural changes can have crucial functional consequences. Understanding this is considered a fundamental step to develop more precise therapeutic approaches in the future.
ADGRV1
A key aspect of Wolff’s research was the detailed study of the ADGRV1 protein. He demonstrated that his team successfully determined, in high resolution, the structure of this protein in its inactive form — an unprecedented result for this GPCR-type adhesion receptor. The analysis revealed how the molecule is organized in the cell membrane and which regions are critical for its stability.
The study shows that as hair cells develop, part of this protein is cleaved — that is, it undergoes natural proteolytic processing — but its signaling region remains active in the mature cell. The finding suggests that ADGRV1 not only acts as a structural element in the formation of cellular connections, but may continue to exert a regulatory function after cochlea maturation.
The researchers also investigated a specific region of the molecule that functions as a “control module,” showing how small chemical modifications — such as phosphorylation — can alter its shape and influence internal cell processes. Furthermore, the team demonstrated that certain mutations associated with deafness alter the stability of this regulatory region, affecting its interaction with proteins in the intracellular signaling pathway.
From isolated structure to intact tissue
In addition to laboratory analyses conducted with purified proteins, Wolff presented experiments conducted directly on mouse cochlear tissue. Using super-resolution microscopy (STED), the team was able to map with nanometric precision the position of these proteins in the stereocilia — microscopic structures responsible for sound detection.
The images revealed differences in the organization of the protein complex between internal hair cells, which detect sound, and external cells, which amplify it. These structural differences helps to explain their functional differences.
The most innovative part of the research involved the use of cryo-electron tomography applied to intact tissues. The technique combines ultra-fast freezing, microscopy under cryogenic conditions, and ultra-thin tissue sections, allowing researchers to observe protein complexes almost exactly as they appear in their natural state.
The researcher notes that the ability to visualize protein complexes at near-atomic resolution directly in the tissue—rather than isolating them from their native biological environment—constitutes a major advancement in the field of structural biology.