FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Cell penetrating peptides and cationic antibacterial peptides: two sides of the same coin
Rodriguez Plaza(*), J. G., Morales-Nava(*), R., Diener(*), C., Schreiber(*), G., Gonzalez(*), Z. D., Lara Ortiz(*), M. T., Ortega Blake(*), I., Pantoja(*), O., Volkmer, R., Klipp(*), E., Herrmann(*), A.; Del Rio(*), G.
J Biol Chem, 289:14448-14457
(2014)

Tags: Peptide Synthesis (Hackenberger/Volkmer)

Abstract: Cell penetrating peptides (CPP) and cationic antibacterial peptides (CAP) have similar physicochemical properties and yet it is not understood how such similar peptides display different activities. To address this question, we used Iztli peptide 1 (IP-1) because it has both CPP and CAP activities. Combining experimental and computational modeling of the internalization of IP-1, we show it is not internalized by receptor-mediated endocytosis, yet it permeates into many different cell types, including fungi and human cells. We also show that IP-1 makes pores in the presence of high electrical potential at the membrane, such as those found in bacteria and mitochondria. These results provide the basis to understand the functional redundancy of CPPs and CAPs.

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle
Sartelet(*), A., Stauber, T., Coppieters(*), W., Ludwig, C. F., Fasquelle(*), C., Druet(*), T., Zhang(*), Z. Y., Ahariz(*), N., Cambisano(*), N., Jentsch, T. J.; Charlier(*), C.
Dis Model Mech, 7:119-128
(2014)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Chloride-proton exchange by the lysosomal anion transporter ClC7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue cattle with a severe symptomatology including perinatal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption.

ClC-7 expression levels critically regulate bone turnover, but not gastric acid secretion
Supanchart(*), C., Wartosch, L., Schlack(*), C., Kühnisch(*), J., Felsenberg, D., Fuhrmann(*), J. C., de Vernejoul(*), M. C., Jentsch, T. J.; Kornak(*), U.
Bone, 58:92-102
(2014)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Mutations in the 2Cl(-)/1H(+)-exchanger ClC-7 impair osteoclast function and cause different types of osteodastrich osteopetrosis. However, it is unknown to what extent ClC-7 function has to be reduced to become rate-limiting for bone resorption. In osteoclasts from osteopetrosis patients expression of the mutated ClC-7 protein did not correlate with disease severity and resorption impairment. Therefore, a series of transgenic mice expressing ClC-7 in osteoclasts at different levels was generated. Crossing of these mice with Clat7(-/-) mutants rescued the osteopetrotic phenotype to variable degrees. One resulting double transgenic line mimicked human autosomal dominant osteopetrosis. The trabecular bone of these mice showed a reduction of osteoblast numbers, osteoid, and osteoblast marker gene expression indicative of reduced osteoblast function. In osteoclasts from these mutants ClC-7 expression levels were 20 to 30% of wildtype levels. These reduced levels not only impaired resorptive activity, but also increased numbers, size and nucleus numbers of osteoclasts differentiated in vitro. Although ClC-7 was expressed in the stomach and PTH levels were high in Clcn7(-/-) mutants loss of ClC-7 did not entail a relevant elevation of gastric pH. In conclusion, we show that in our model a reduction of ClC-7 function by approximately 70% is sufficient to increase bone mass, but does not necessarily enhance bone formation. ClC-7 does not appear to be crucially involved in gastric acid secretion, which explains the absence of an osteopetrorickets phenotype in CLCN7-related osteopetrosis.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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