TY - GEN A1 - Schieferdecker, Anne A1 - Wendler, Petra T1 - Structural mapping of missense mutations in the Pex1/Pex6 complex T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast scPex1/scPex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1072 KW - Zellweger syndrome spectrum disorder (ZSSD) KW - Zellweger KW - structure KW - Pex1 KW - Pex6 KW - mutation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-472843 SN - 1866-8372 IS - 1072 ER - TY - JOUR A1 - Schieferdecker, Anne A1 - Wendler, Petra T1 - Structural Mapping of Missense Mutations in the Pex1/Pex6 Complex JF - International journal of molecular sciences N2 - Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast scPex1/scPex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients. KW - Zellweger syndrome spectrum disorder (ZSSD) KW - Zellweger KW - structure KW - Pex1 KW - Pex6 KW - mutation Y1 - 2019 U6 - https://doi.org/10.3390/ijms20153756 SN - 1422-0067 VL - 20 IS - 15 PB - MDPI CY - Basel ER - TY - JOUR A1 - Kötzing, Timo A1 - Lagodzinski, Gregor J. A. A1 - Lengler, Johannes A1 - Melnichenko, Anna T1 - Destructiveness of lexicographic parsimony pressure and alleviation by a concatenation crossover in genetic programming JF - Theoretical computer science N2 - For theoretical analyses there are two specifics distinguishing GP from many other areas of evolutionary computation: the variable size representations, in particular yielding a possible bloat (i.e. the growth of individuals with redundant parts); and also the role and the realization of crossover, which is particularly central in GP due to the tree-based representation. Whereas some theoretical work on GP has studied the effects of bloat, crossover had surprisingly little share in this work.
We analyze a simple crossover operator in combination with randomized local search, where a preference for small solutions minimizes bloat (lexicographic parsimony pressure); we denote the resulting algorithm Concatenation Crossover GP. We consider three variants of the well-studied MAJORITY test function, adding large plateaus in different ways to the fitness landscape and thus giving a test bed for analyzing the interplay of variation operators and bloat control mechanisms in a setting with local optima. We show that the Concatenation Crossover GP can efficiently optimize these test functions, while local search cannot be efficient for all three variants independent of employing bloat control. (C) 2019 Elsevier B.V. All rights reserved. KW - genetic programming KW - mutation KW - theory KW - run time analysis Y1 - 2020 U6 - https://doi.org/10.1016/j.tcs.2019.11.036 SN - 0304-3975 VL - 816 SP - 96 EP - 113 PB - Elsevier CY - Amsterdam ER -