A5065079065- Renal Diseases and Glomerulopathies
- Autoimmune Bullous Skin Diseases
- Ion Transport and Channel Regulation
- Enzyme Structure and Function
- Vasculitis and related conditions
- Platelet Disorders and Treatments
- Renal and related cancers
- Complement system in diseases
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- RNA and protein synthesis mechanisms
- Genetic and Kidney Cyst Diseases
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Biomedical Research and Pathophysiology
- Protein Structure and Dynamics
- Ion channel regulation and function
- Chronic Kidney Disease and Diabetes
- ATP Synthase and ATPases Research
- Tuberculosis Research and Epidemiology
- Single-cell and spatial transcriptomics
- Amyloidosis: Diagnosis, Treatment, Outcomes
- RNA modifications and cancer
- Photoreceptor and optogenetics research
- Organ Transplantation Techniques and Outcomes
- Hydrogen Storage and Materials
Universität Hamburg
2018-2024
University Medical Center Hamburg-Eppendorf
2018-2024
Hamburg Institut (Germany)
2024
Aarhus University
2013-2022
Phillips University
2022
Medizinische Hochschule Hannover
2022
Karolinska Institutet
2015-2017
Centre for Structural Systems Biology
2015-2017
Danish National Research Foundation
2013-2016
European Molecular Biology Laboratory
2016
The Na(+), K(+)-adenosine triphosphatase (ATPase) maintains the electrochemical gradients of Na(+) and K(+) across plasma membrane--a prerequisite for electrical excitability secondary transport. Hitherto, structural information has been limited to K(+)-bound or ouabain-blocked forms. We present crystal structure a Na(+)-bound K(+)-ATPase as determined at 4.3 Å resolution. Compared with form, large conformational changes are observed in α subunit whereas β γ structures maintained. locations...
Proteins that contain metal cofactors are expected to be highly radiation sensitive since the degree of X-ray absorption correlates with presence high-atomic-number elements and energy. To explore effects local damage in serial femtosecond crystallography (SFX), Clostridium ferredoxin was used as a model system. The protein contains two [4Fe-4S] clusters serve probes for radiation-induced electronic structural changes. High-dose room-temperature SFX datasets were collected at Linac Coherent...
The stability and homogeneity of a protein sample is strongly influenced by the composition buffer that in. A quick easy approach to identify which increases possibly conformational fluorescence-based thermal-shift assay (Thermofluor). Here, novel 96-condition screen for Thermofluor experiments presented consists additive parts. comprises 23 different buffers includes small-molecule additives such as salts nucleotide analogues. utilization components increase thermal frequently results in...
Mitochondrial polycistronic transcripts are extensively processed to give rise functional mRNAs, rRNAs and tRNAs; starting with the release of tRNA elements through 5'-processing by RNase P (MRPP1/2/3-complex) 3'-processing Z (ELAC2). Here, we show using in vitro experiments that MRPP1/2 is not only a component mitochondrial but it retains product from step significantly enhances efficiency ELAC2-catalyzed for 17 22 tRNAs encoded human genome. Furthermore, after ELAC2 processing presents...
Primary membranous nephropathy (MN) is caused by circulating autoantibodies binding to antigens on the podocyte surface. PLA2R1 main target antigen in 70%-80% of cases, but pathogenesis unresolved 10%-15% patients.We used native western blotting identify IgG4 autoantibodies, which bind an endogenously expressed membranes, serum index patient with MN. These were immunoprecipitate antigen, and mass spectrometry was Netrin G1 (NTNG1). Using blot ELISA, NTNG1 analyzed cohorts 888 patients MN or...
Membranous nephropathy (MN) is an autoimmune kidney disease characterized by immune deposits in the glomerular basement membrane. Circulating anti-phospholipase A 2 receptor 1 (PLA R1) antibodies are detectable 70%-80% of patients with MN, but experimental evidence pathogenicity has been lacking. This study demonstrates human anti-PLA R1 minipigs, a model for MN that intrinsically expresses PLA on podocytes. After passive transfer antibody-containing plasma from R1-associated to were...
Mitochondrial RNA polymerase produces long polycistronic precursors that contain the mRNAs, rRNAs and tRNAs needed for mitochondrial translation. RNase P (mt-RNase P) initiates maturation of by cleaving at 5′ ends tRNAs. Human mt-RNase is only active as a tripartite complex (mitochondrial proteins 1–3; MRPP1-3), whereas plant trypanosomal Ps (PRORPs)—albeit homologous to MRPP3—are single proteins. The reason this discrepancy has so far remained obscure. Here, we present crystal structure...
Significance Statement Phospholipase A 2 receptor 1 (PLA R1) is the major target of autoimmunity in membranous nephropathy. Anti-PLA R1 antibody levels predict treatment response and outcome this disease. Earlier studies identified three epitope regions PLA proposed that having antibodies against more than one region had prognostic relevance. In prospective study a cohort 150 patients with newly diagnosed nephropathy, authors fourth targeted by anti-PLA antibodies. They also found all sera...
Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered have unspecified IgG4-driven genesis, while secondary associated with other diseases, most notably cancer, not linked IgG4. Immunologic mechanisms malignancy-associated are assumed be different, however, this never systematically evaluated. The identification Phospholipase A2 Receptor 1 (PLA2R1)...
Background Thrombospondin type 1 domain–containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown. Methods We performed an silico analysis of multidomain structure, expressed folded domains HEK293 cells, and tested for domain reactivity with 31 serum samples from patients THSD7A-associated MN using Western native blotting. Immunogenicity antigen was further investigated...
Kidney organoids are a promising model to study kidney disease, but their use is constrained by limited knowledge of functional protein expression profile. Here, we define the organoid proteome and transcriptome trajectories over culture duration upon exposure TNFα, cytokine stressor. Older increase deposition extracellular matrix decrease glomerular proteins. Single cell integration reveals that most changes localize podocytes, tubular stromal cells. TNFα treatment results in 322...
Background Membranous nephropathy (MN) is an autoimmune disease induced by circulating antibodies against the podocyte protein phospholipase A2 receptor 1 (PLA2R1-ab) in 80% of patients and represents leading cause nephrotic syndrome adults. PLA2R1-ab levels correlate with activity treatment response. However, their predictive role for long-term renal outcome not clear. Methods The aim this prospective observational multicenter study was to investigate at time diagnosis a cohort 243 newly...
Na + ,K -ATPase is responsible for the transport of and K across plasma membrane in animal cells, thereby sustaining vital electrochemical gradients that energize channels secondary transporters. The crystal structure has previously been elucidated using enzyme from native sources such as porcine kidney shark rectal gland. Here, isolation, crystallization first determination bovine a high-affinity E2–BeF 3 − –ouabain complex with bound magnesium are described. Crystals belonging to...
Membranous nephropathy (MN) constitutes a major cause of nephrotic syndrome (NS) in adults. After kidney transplantation (KTx), both recurrent and de novo MN has been reported. In addition to PLA2R THSD7A, recent identification neural EGFL-like-1 protein, NELL1, as potential disease antigen enriched our understanding pathogenesis. To date, NELL1-positive only described native kidneys, but never diagnosed renal allografts. We here report on 56-year-old male transplant recipient suffering from...
Membrane proteins are key players in biological systems, mediating signalling events and the specific transport of e.g. ions metabolites. Consequently, membrane targeted by a large number currently approved drugs. Understanding their functions molecular mechanisms is greatly dependent on structural information, not least complexes with functionally or medically important ligands. Structure determination, however, hampered difficulty obtaining well diffracting, macroscopic crystals. Here,...