ORCID Profile
0000-0001-5644-045X
Current Organisation
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Publisher: Elsevier BV
Date: 08-2014
Publisher: Elsevier BV
Date: 07-2020
Publisher: MDPI AG
Date: 05-10-2022
Abstract: The complex host interaction network of human cytomegalovirus (HCMV) involves the regulatory protein kinase pUL97, which represents a viral cyclin-dependent kinase (CDK) ortholog. pUL97 interacts with the three human cyclin types T1, H, and B1, whereby the binding region of cyclin T1 and the pUL97 oligomerization region were both assigned to amino acids 231-280. We further addressed the question of whether HCMVs harboring mutations in ORF-UL97, i.e., short deletions or resistance-conferring point mutations, are affected in the interaction with human cyclins and viral replication. To this end, clinically relevant UL97 drug-resistance-conferring mutants were analyzed by whole-genome sequencing and used for genetic marker transfer experiments. The recombinant HCMVs indicated conservation of pUL97–cyclin interaction, since all viral UL97 point mutants continued to interact with the analyzed cyclin types and exerted wild-type-like replication fitness. In comparison, recombinant HCMVs UL97 Δ231-280 and also the smaller deletion Δ236-275, but not Δ241-270, lost interaction with cyclins T1 and H, showed impaired replication efficiency, and also exhibited reduced kinase activity. Moreover, a cellular knock-out of cyclins B1 or T1 did not alter HCMV replication phenotypes or pUL97 kinase activity, possibly indicating alternative, compensatory pUL97–cyclin interactions. In contrast, however, cyclin H knock-out, similar to virus deletion mutants in the pUL97–cyclin H binding region, exhibited strong defective phenotypes of HCMV replication, as supported by reduced pUL97 kinase activity in a cyclin H-dependent coexpression setting. Thus, cyclin H proved to be a very relevant determinant of pUL97 kinase activity and viral replication efficiency. As a conclusion, the results provide evidence for the functional importance of pUL97–cyclin interaction. High selective pressure on the formation of pUL97–cyclin complexes was identified by the use of clinically relevant mutants.
Publisher: Elsevier BV
Date: 08-2018
Publisher: MDPI AG
Date: 18-12-2013
DOI: 10.3390/V5123213
Publisher: Elsevier BV
Date: 07-2013
Publisher: American Chemical Society (ACS)
Date: 08-11-2021
DOI: 10.1021/ACS.JMEDCHEM.1C01574
Abstract: The family of neuropeptide Y (NPY) receptors comprises four subtypes (Y
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2022
DOI: 10.1101/2022.04.04.22273309
Abstract: PPFIBP1 encodes for the liprin-β1 protein which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster . By exome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 14 in iduals from 10 unrelated families. The in iduals presented with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Further common clinical findings included muscular hypertonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired hearing and vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM-domain region that is essential for protein-protein interaction. For further insight in the effects of PPFIBP1 loss-of-function, we performed automated behavioural phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model which revealed defects in spontaneous and light-induced behaviour and confirmed resistance to the acetylcholinesterase inhibitor aldicarb suggesting a defect in the neuronal presynaptic zone. In conclusion, we present bi-allelic loss-of-function variants in PPFIBP1 as a novel cause of an autosomal recessive neurodevelopmental disorder.
No related grants have been discovered for Heinrich Sticht.