TY  - JOUR
A1  - Aster, Hans-Christoph
A1  - Romanos, Marcel
A1  - Walitza, Susanne
A1  - Gerlach, Manfred
A1  - Mühlberger, Andreas
A1  - Rizzo, Albert
A1  - Andreatta, Marta
A1  - Hasenauer, Natalie
A1  - Hartrampf, Philipp E.
A1  - Nerlich, Kai
A1  - Reiners, Christoph
A1  - Lorenz, Reinhard
A1  - Buck, Andreas K.
A1  - Deserno, Lorenz
T1  - Responsivity of the striatal dopamine system to methylphenidate — A within-subject I-123-β-CIT-SPECT study in male children and adolescents with attention-deficit/hyperactivity disorder
JF  - Frontiers in Psychiatry
N2  - Background:
Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning.


Methods
Thirteen adolescent male patients (9–16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH.


Results
On-MPH status was associated with a highly significant change (−29.9%) of striatal DAT BP as compared to off-MPH (t = −4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04).


Conclusion
Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.
KW  - methylphenidate
KW  - attention deficit/hyperactivity disorder (ADHD)
KW  - striatum
KW  - single photon emission computed tomography (SPECT)
KW  - responsivity
KW  - caudate nucleus
KW  - dopamine transporter (DAT)
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270862
SN  - 1664-0640
VL  - 13
ER  - 
TY  - JOUR
A1  - Ries, Lena K.
A1  - Liess, Anna K. L.
A1  - Feiler, Christian G.
A1  - Spratt, Donald E.
A1  - Lowe, Edward D.
A1  - Lorenz, Sonja
T1  - Crystal structure of the catalytic C‐lobe of the HECT‐type ubiquitin ligase E6AP
JF  - Protein Science
N2  - The HECT‐type ubiquitin ligase E6AP (UBE3A) is critically involved in several neurodevelopmental disorders and human papilloma virus‐induced cervical tumorigenesis; the structural mechanisms underlying the activity of this crucial ligase, however, are incompletely understood. Here, we report a crystal structure of the C‐terminal lobe (“C‐lobe”) of the catalytic domain of E6AP that reveals two molecules in a domain‐swapped, dimeric arrangement. Interestingly, the molecular hinge that enables this structural reorganization with respect to the monomeric fold coincides with the active‐site region. While such dimerization is unlikely to occur in the context of full‐length E6AP, we noticed a similar domain swap in a crystal structure of the isolated C‐lobe of another HECT‐type ubiquitin ligase, HERC6. This may point to conformational strain in the active‐site region of HECT‐type ligases with possible implications for catalysis.

Significance Statement
The HECT‐type ubiquitin ligase E6AP has key roles in human papilloma virus‐induced cervical tumorigenesis and certain neurodevelopmental disorders. Here, we present a crystal structure of the C‐terminal, catalytic lobe of E6AP, providing basic insight into the conformational properties of this functionally critical region of HECT‐type ligases.
KW  - dimerization
KW  - domain swapping
KW  - E3 enzyme
KW  - UBE3A
KW  - X‐ray crystallography
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214812
VL  - 29
IS  - 6
SP  - 1550
EP  - 1554
ER  - 
TY  - JOUR
A1  - Ries, Lena K.
A1  - Sander, Bodo
A1  - Deol, Kirandeep K.
A1  - Letzelter, Marie-Annick
A1  - Strieter, Eric Robert
A1  - Lorenz, Sonja
T1  - Analysis of ubiquitin recognition by the HECT ligase E6AP provides insight into its linkage specificity
JF  - Journal of Biological Chemistry
N2  - Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin-conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.
KW  - ubiquitin
KW  - ubiquitin ligase
KW  - ubiquitylation (ubiquitination)
KW  - post-translational modification
KW  - enzyme mechanism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226207
VL  - 294
IS  - 15
ER  - 
TY  - JOUR
A1  - Müller, Stefanie H.
A1  - Girard, Simon L.
A1  - Hopfner, Franziska
A1  - Merner, Nancy D.
A1  - Bourassa, Cynthia V.
A1  - Lorenz, Delia
A1  - Clark, Lorraine N.
A1  - Tittmann, Lukas
A1  - Soto-Ortolaza, Alexandra I.
A1  - Klebe, Stephan
A1  - Hallett, Mark
A1  - Schneider, Susanne A.
A1  - Hodgkinson, Colin A.
A1  - Lieb, Wolfgang
A1  - Wszolek, Zbigniew K.
A1  - Pendziwiat, Manuela
A1  - Lorenzo-Betancor, Oswaldo
A1  - Poewe, Werner
A1  - Ortega-Cubero, Sara
A1  - Seppi, Klaus
A1  - Rajput, Alex
A1  - Hussl, Anna
A1  - Rajput, Ali H.
A1  - Berg, Daniela
A1  - Dion, Patrick A.
A1  - Wurster, Isabel
A1  - Shulman, Joshua M.
A1  - Srulijes, Karin
A1  - Haubenberger, Dietrich
A1  - Pastor, Pau
A1  - Vilariño-Güell, Carles
A1  - Postuma, Ronald B.
A1  - Bernard, Geneviève
A1  - Ladwig, Karl-Heinz
A1  - Dupré, Nicolas
A1  - Jankovic, Joseph
A1  - Strauch, Konstantin
A1  - Panisset, Michel
A1  - Winkelmann, Juliane
A1  - Testa, Claudia M.
A1  - Reischl, Eva
A1  - Zeuner, Kirsten E.
A1  - Ross, Owen A.
A1  - Arzberger, Thomas
A1  - Chouinard, Sylvain
A1  - Deuschl, Günther
A1  - Louis, Elan D.
A1  - Kuhlenbäumer, Gregor
A1  - Rouleau, Guy A.
T1  - Genome-wide association study in essential tremor identifies three new loci
JF  - Brain
N2  - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
KW  - quality-control
KW  - disease
KW  - tool
KW  - movement disorders
KW  - genome-wide association study
KW  - tremor
KW  - genetics
KW  - essential tremor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541
VL  - 139
ER  - 
TY  - JOUR
A1  - Stritt, Simon
A1  - Nurden, Paquita
A1  - Favier, Remi
A1  - Favier, Marie
A1  - Ferioli, Silvia
A1  - Gotru, Sanjeev K.
A1  - van Eeuwijk, Judith M.M.
A1  - Schulze, Harald
A1  - Nurden, Alan T.
A1  - Lambert, Michele P.
A1  - Turro, Ernest
A1  - Burger-Stritt, Stephanie
A1  - Matsushita, Masayuki
A1  - Mittermeier, Lorenz
A1  - Ballerini, Paola
A1  - Zierler, Susanna
A1  - Laffan, Michael A.
A1  - Chubanov, Vladimir
A1  - Gudermann, Thomas
A1  - Nieswandt, Bernhard
A1  - Braun, Attila
T1  - Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg\(^{2+}\) homeostasis and cytoskeletal architecture
JF  - Nature Communications
N2  - Mg\(^{2+}\) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg\(^{2+}\)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7\(^{fl/fl-Pf4Cre}\)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7\(^{fl/fl-Pf4Cre}\) MKs, which is rescued by Mg\(^{2+}\) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
KW  - Cytoskeleton
KW  - homeostasisIon channels
KW  - thrombopoiesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173843
VL  - 7
ER  - 
TY  - JOUR
A1  - Deol, Kirandeep K.
A1  - Lorenz, Sonja
A1  - Strieter, Eric R.
T1  - Enzymatic logic of ubiquitin chain assembly
JF  - Frontiers in Physiology
N2  - Protein ubiquitination impacts virtually every biochemical pathway in eukaryotic cells. The fate of a ubiquitinated protein is largely dictated by the type of ubiquitin modification with which it is decorated, including a large variety of polymeric chains. As a result, there have been intense efforts over the last two decades to dissect the molecular details underlying the synthesis of ubiquitin chains by ubiquitin-conjugating (E2) enzymes and ubiquitin ligases (E3s). In this review, we highlight these advances. We discuss the evidence in support of the alternative models of transferring one ubiquitin at a time to a growing substrate-linked chain (sequential addition model) versus transferring a pre-assembled ubiquitin chain (en bloc model) to a substrate. Against this backdrop, we outline emerging principles of chain assembly: multisite interactions, distinct mechanisms of chain initiation and elongation, optimal positioning of ubiquitin molecules that are ultimately conjugated to each other, and substrate-assisted catalysis. Understanding the enzymatic logic of ubiquitin chain assembly has important biomedical implications, as the misregulation of many E2s and E3s and associated perturbations in ubiquitin chain formation contribute to human disease. The resurgent interest in bifunctional small molecules targeting pathogenic proteins to specific E3s for polyubiquitination and subsequent degradation provides an additional incentive to define the mechanisms responsible for efficient and specific chain synthesis and harness them for therapeutic benefit.
KW  - ubiquitin
KW  - E2 conjugating enzyme
KW  - E3 ligating enzyme
KW  - sequential addition
KW  - en bloc transfer
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201731
VL  - 10
IS  - 835
ER  - 
TY  - JOUR
A1  - Dammert, Marcel A.
A1  - Brägelmann, Johannes
A1  - Olsen, Rachelle R.
A1  - Böhm, Stefanie
A1  - Monhasery, Niloufar
A1  - Whitney, Christopher P.
A1  - Chalishazar, Milind D.
A1  - Tumbrink, Hannah L.
A1  - Guthrie, Matthew R.
A1  - Klein, Sebastian
A1  - Ireland, Abbie S.
A1  - Ryan, Jeremy
A1  - Schmitt, Anna
A1  - Marx, Annika
A1  - Ozretić, Luka
A1  - Castiglione, Roberta
A1  - Lorenz, Carina
A1  - Jachimowicz, Ron D.
A1  - Wolf, Elmar
A1  - Thomas, Roman K.
A1  - Poirier, John T.
A1  - Büttner, Reinhard
A1  - Sen, Triparna
A1  - Byers, Lauren A.
A1  - Reinhardt, H. Christian
A1  - Letai, Anthony
A1  - Oliver, Trudy G.
A1  - Sos, Martin L.
T1  - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
JF  - Nature Communications
N2  - MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
KW  - genetic engineering
KW  - oncogenes
KW  - small-cell lung cancer
KW  - targeted therapies
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223569
VL  - 10
ER  - 
TY  - JOUR
A1  - Joos, J. P.
A1  - Saadatmand, A. R.
A1  - Schnabel, C.
A1  - Viktorinová, I.
A1  - Brand, T.
A1  - Kramer, M.
A1  - Nattel, S.
A1  - Dobrev, D.
A1  - Tomancak, P.
A1  - Backs, J.
A1  - Kleinbongard, P.
A1  - Heusch, G.
A1  - Lorenz, K.
A1  - Koch, E.
A1  - Weber, S.
A1  - El-Armouche, A.
T1  - Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila
JF  - Scientific Reports
N2  - Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.
KW  - cardiac hypertrophy
KW  - epigenetics
KW  - heart failure
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323637
VL  - 8
ER  -