Biology subjects

Paterou, A.

Publications and source records attributed to Paterou, A..

4 recordsLinked to original sources

bioRxiv2026

Staged maturation converts a probasal body template complex into a nucleation-competent basal plate

The central pair (CP) of microtubules is essential for flagellar motility, yet the molecular events underpinning its nucleation remain poorly defined. Here, we report a comprehensive screen of flagellar transition zone proteins that identifies new central pair assembly proteins (CPAPs). Using expansion microscopy, we reveal a concentric architecture at the basal plate, with themelin and basalin forming nested punctae with radial symmetry surrounding a central core containing TZP103.8, TZP48 and {gamma}-tubulin. A subset of CPAPs pre-assemble at the probasal body, a precursor structure that has not yet built a flagellum, with themelin functioning as the architectural template and master recruiter, and TZP103.8 and {gamma}-tubulin IFT-dependant addition being the final step of basal plate activation. Strikingly, in the absence of TZP103.8, {gamma}-tubulin still reaches the basal plate but is insufficient for central pair nucleation. We propose the staged assembly of CPAPs progressively constructs a structural template that geometrically constrains {gamma}-tubulin into the positions and orientations required for CP nucleation.

cell biology↗

bioRxiv2023

Unlocking Trypanosome Biology: A Comprehensive Protein-Tagging Toolkit for Localization and Functional Analysis

African trypanosomes are medically important parasites that cause Sleeping sickness in humans and nagana in animals. In addition to their pathogenic role, they have emerged as valuable model organisms for studying fundamental biological processes. Protein tagging is a powerful tool for investigating protein localization and function. In a previous study, we developed two plasmids for rapid and reproducible protein tagging in trypanosomes, which enabled the localisation of all proteins in the trypanosome cell. However, the limited selection of fluorescent protein tags and selectable markers restricted the flexibility of this approach. Here, we present an expanded set of >100 vectors that utilizes universal primer annealing sequences, enabling protein tagging with a range of fluorescent and biochemical tags using five different selection markers. We evaluated the suitability of various fluorescent proteins for live cell imaging and determined their brightness and stability under different fixation conditions. Finally, we determined the optimal fluorescent protein for a set of specific experimental conditions demonstrating the utility of this toolkit.

cell biology↗

bioRxiv2021

HLA class II mediates type 1 diabetes risk by anti-insulin repertoire selection

Type 1 diabetes (T1D) is a common autoimmune disorder characterized by the destruction of insulin-secreting pancreatic {beta} cells [1], in which polymorphism of the human leukocyte antigen (HLA) class II region is the major genetic risk factor [2, 3, 4]. However, how variation in class II molecules alters T1D risk remains a longstanding question. Here we show how T1D risk due to HLA class II haplotype combinations [5] correlates with the frequency of negatively charged sequences in the CDR3{beta} region of CD4+ T cell receptor (TCR) repertoires purified from peripheral blood. These sequences are known to be common in receptors that bind insulin B:9-23 [6], the primary autoantigen in T1D. We also show the same effect in circulating activated CD4+ T cells from newly-diagnosed T1D cases, and in islet-infiltrating T cells from patients with active T1D. Furthermore, we demonstrate that the proportion of insulin-reactive CD4+ T cells present in islets is predicted by the frequency of these negatively charged CDR3{beta} amino acid sequences. Our results suggest diagnostic uses of T cell repertoire profiling in early detection of insulin autoimmunity, and inform ongoing efforts to improve tolerance induction to insulin and prevention of T1D [7].

genomics↗

bioRxiv2019

Peripheral tolerance to insulin is encoded by mimicry in the microbiome

How organisms achieve sustained peripheral tolerance throughout their lifetime, a correct immune discrimination between self and non-self, remains poorly understood. Host-microbiome interactions carry fundamental information that facilitates this process. We hypothesize that commensal microbes are under evolutionary pressure to develop epitopes that, when presented along with other antigens from their own bacterial community, lead to an overall tolerogenic self classification by the host immune system. Hosts, which have co-evolved with commensals, may rely on mimotopes, bacterial epitopes that are indistinguishable from key self epitopes, as a homeostatic feedback mechanism to establish and maintain tolerance. Using a probabilistic sequence model of peptide mimicry, we show that the gut microbiome contains a set of genes that are likely to trigger identical immune responses to insulin B 9-25, a widely distributed self epitope across tissues and the primary autoantigen in type 1 diabetes. Similarities in the antigen receptor sequences determined from CD4 T cells reacting to insulin epitopes and mimotopes provide experimental evidence for mimicry. All predicted high posterior probability mimotopes belong to the transketolase superfamily, an enzyme that allows efficient harvest of commensal-derived sugar polymers and dietary fibre, an advantage during host colonisation. Microbial transketolase upregulation during infant weaning coincides in time with the peak in autoantibody development against insulin. Abundance changes in bacterial genera that carry these mimotopes have also been observed to precede disease diagnosis. Our findings suggest gut dysbiosis followed by immune response to insulin mimotopes as a primary cause of type 1 diabetes, and may contribute towards unraveling similar causal patterns in a wide variety of disorders.

immunology↗