Biology subjects

Van Wielendaele, P.

Publications and source records attributed to Van Wielendaele, P..

3 recordsLinked to original sources

bioRxiv2026

The hearing-essential intracellular domain of PCDH15 reveals a new layer of auditory mechanotransduction

Current models of mechanotransduction in inner-ear hair cells explain how force is transmitted through the extracellular tip link but provide little insight into how force is propagated beneath the plasma membrane. Although the CD2 isoform of PCDH15 has been shown to be essential for hearing in mature mammalian hair cells, its structural and mechanical properties have remained largely unknown. Here, we combine computational sequence analysis, orthogonal biophysical characterization and small-angle X-ray scattering (SAXS) to show that the hearing-essential CD2 intracellular domain is an intrinsically disordered region (IDR) that behaves as a highly expanded acidic polyampholyte. CD2 remains predominantly monomeric in solution and occupies a larger conformational space at physiological-like ionic strength, whereas inclusion of the isoform-shared common region increases self-association. CD2 also contains a conserved regulatory interaction platform, providing a potential link between its polymer properties and cellular regulation. Together, these findings identify the CD2 intracellular domain as a polymer with biophysical properties consistent with a mechanically responsive structural element. Furthermore, they provide a framework for investigating how intracellular polymer mechanics may contribute to force transmission and adaptation in auditory mechanotransduction.

biophysics↗

bioRxiv2025

Structural basis for the inhibition of Trypanosoma brucei enolase by a camelid single-domain antibody

Trypanosoma brucei is an extracellular protozoan that causes neglected tropical diseases in both humans and livestock. The parasite has a bipartite life cycle involving an insect vector and a mammalian host. Within the latter, it mainly thrives as a blood-borne parasite that relies on glycolysis to support its energy metabolism. It is for this reason that trypanosomal glycolytic enzymes have been investigated as potential targets for the development of trypanosome-killing drugs. Recent work from our lab has shown that they are also interesting biomarkers for the detection of active trypanosome infections. T. brucei enolase (TbrENO) is a trypanosomal glycolytic enzyme that has gathered interest in both drug and diagnostics development. In this paper, we report the discovery of a camelid single domain antibody (sdAb aka nanobody) that specifically recognises and inhibits TbrENO. The sdAbs inhibitory mechanism is unraveled through a combination of protein biochemistry, biophysics, and structural biology. Author summaryTrypanosoma brucei is a unicellular parasite that lives in the bloodstream of humans and animals, where it causes serious but often overlooked diseases. Because it depends heavily on breaking down glucose to produce energy, the parasites glucose-processing proteins (called glycolytic enzymes) have become important targets for both new treatments and improved diagnostic tools. One of these proteins, called T. brucei enolase (TbrENO), has recently drawn attention for its potential in drug development and disease detection. In this study, we discovered a special type of antibody, known as a camelid single-domain antibody (sdAb aka nanobody), that can specifically recognize and block the activity of TbrENO. We employed a combination of various laboratory techniques to understand exactly how the sdAb binds to and inhibits the enzyme. Our findings provide new insight into how TbrENO can be inhibited in a way that does not require active site binding and highlight the value of sdAbs as precise tools for targeting key parasite proteins.

bioengineering↗

bioRxiv2024

Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody

African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.

biochemistry↗