Biology subjects

Haase, D.

Publications and source records attributed to Haase, D..

3 recordsLinked to original sources

bioRxiv2022

Tetraspanner-based nanodomains modulate BAR domain-induced membrane curvature

Topography is a critical feature driving formation and dynamics of protein and lipid domains within biological membranes. The yeast plasma membrane (PM) has provided a powerful model system to study lateral domain formation, including characteristic BAR domain-induced PM furrows. Currently, it is not clear how the components involved in the establishment of these furrows cooperate to precisely regulate local PM topography. Here we report opposing functions for the Sur7 and Nce102 families of tetraspanner proteins in modulating membrane curvature and domain topography. Using STED nanoscopy and freeze-fracture EM we found that Sur7 tetraspanners form multimeric strands at the upper edges of PM furrows, which counteract the forces exerted by BAR domain proteins and prevent membrane tubulation. In contrast, Nce102 tetraspanners are located basal to the Sur7 proteins and promote BAR domain-induced curvature. The segregation of the two tetraspanner-based nanodomains is further supported by differential distribution of ergosterol to the upper edge of furrows and PIP2 lipids at the furrow base. These findings suggest a general role of tetraspanner proteins in sculpting local membrane domains.

cell biology↗

bioRxiv2019

Implications of TP53 Allelic State for Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes

TP53 mutations are associated with poor clinical outcomes and treatment resistance in myelodysplastic syndromes. However, the biological and clinical relevance of the underlying mono- or bi-allelic state of the mutations is unclear. We analyzed 3,324 MDS patients for TP53 mutations and allelic imbalances of the TP53 locus and found that 1 in 3 TP53-mutated patients had mono-allelic targeting of the gene whereas 2 in 3 had multiple hits consistent with bi-allelic targeting. The established associations for TP53 with complex karyotype, high-risk presentation, poor survival and rapid leukemic transformation were specific to patients with multi-hit state only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System, while mono-allelic patients did not differ from TP53 wild-type patients. The separation by allelic state was retained in therapy-related MDS. Findings were validated in a cohort of 1,120 patients. Ascertainment of TP53 allelic state is critical for diagnosis, risk estimation and prognostication precision in MDS, and future correlative studies of treatment response should consider TP53 allelic state.

genomics↗

bioRxiv2018

Lateral plasma membrane compartmentalization links protein function and turnover

Biological membranes organize their proteins and lipids into nano- and microscale patterns. In the yeast plasma membrane (PM) constituents segregate into a large number of distinct domains. However, if and how this intricate patchwork contributes to biological functions at the PM is still poorly understood. Here, we reveal an elaborate interplay between PM compartmentalization, biochemical function and endocytic turnover. Using the methionine permease Mup1 as model system we demonstrate that this transporter segregates into PM clusters. Clustering requires sphingolipids, the tetraspanner Nce102 and TORC2 signaling. Importantly, we show that during substrate transport, a simple conformational change in Mup1 mediates rapid relocation into a unique disperse network at the PM. Clustered Mup1 is protected from turnover, whereas relocated Mup1 actively recruits the endocytic machinery thereby initiating its own turnover. Our findings suggest that lateral compartmentalization provides an important regulatory link between function and turnover of PM proteins.

cell biology↗