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PD Dr. Martina Mühlenhoff

 

Dr. rer. nat.

Diplom-Biochemikerin

 

 

Büro: Geb. J3, Ebene 04, Raum 1310

Labor: Geb. J3, Ebene 04, Raum 1070

Tel.: +49(0)511/532-9807 (Büro), -9842 (Labor)

FAX: +49(0)511/532-8801

 

E-Mail: Muehlenhoff.Martina(at)mh-hannover.de

 

 

 

 

 

Research interests

 

- Biosynthesis and functional role of polysialic acid

 

Identification and characterization of polysialic acid carrier proteins. Biological role of the two mammalian polysialyltransferases ST8SiaII and ST8SiaIV.

 

Key references:

 

Werneburg S, Buettner FFR, Mühlenhoff M, Hildebrandt H. (2015) Polysialic acid modification of the synaptic cell adhesion molecule SynCAM 1 in human embryonic stem cell-derived oligodendrocyte precursor cells. Stem Cell Res. 14:339–346. doi: 10.1016/j.scr.2015.03.001

 

Werneburg S, Mühlenhoff M, Stangel M, Hildebrandt H (2015) Polysialic acid on SynCAM 1 in NG2 cells and on neuropilin-2 in microglia is confined to intracellular pools that are rapidly depleted upon stimulation. Glia 63 (7): 1240-1255. doi: 10.1002/glia.22815

 

Mühlenhoff M., Rollenhagen M., Werneburg S, Gerardy-Schahn R. Hildebrandt H. (2013) Polysialic acid - versatile modification of NCAM, SynCAM 1 and neuropilin-2. Neurochem Res. 38 (6):1134-1143. doi: 10.1007/s11064-013-0979-2

 

Rollenhagen M, Büttner FF, Reismann M, Jirmo AC, Grove M, Behrens GMN, Gerardy-Schahn R, Hanisch F-G, Mühlenhoff M (2013) Polysialic Acid On Neuropilin-2 Is Exclusively Synthesized By The Polysialyltransferase ST8SiaIV And Attached To Mucin-Type O- Glycans Located Between b2 And c Domain. J Biol Chem.

 

Galuska, S.P., Rollenhagen, M., Kaup, M., Eggers, K., Oltmann-Norden, I., Schiff, M., Hartmann, M., Weinhold, B., Hildebrandt, H., Geyer, R., Mühlenhoff, M.*, and Geyer H. (2010). Synaptic cell adhesion molecule SynCAM 1 is a target for polysialylation in postnatal mouse brain. Proc. Natl. Acad. Sci. USA, 107, 10250-10255.

*equally contributing last and co-corresponding author

 

Oltmann-Norden, I., Galuska, S.P., Hildebrandt, H., Geyer, R., Gerardy-Schahn, R., Geyer, H., and Mühlenhoff, M. (2008). Impact of the polysialyltransferases ST8SiaII and ST8SiaIV on polysialic acid synthesis during postnatal mouse brain development. J. Biol. Chem. 283, 1463-71.

 

Galuska, S. P., Oltmann-Norden, I., Geyer, H., Weinhold, B., Kuchelmeister, K., Hildebrandt, H., Gerardy-Schahn, R., Geyer, R., and Mühlenhoff, M. (2006). Polysialic acid profiles of mice expressing variant allelic combinations of the polysialyltransferases ST8SiaII and ST8SiaIV. J. Biol. Chem. 281, 31605-31615.

 

 

- O-acetylation of sialic and polysialic acids

 

Identification and characterization of bacterial and mammalian sialate O-acetyltransferases (SIATs)

 

Key references:

 

Baumann A.-M.T., Bakkers M.J.G., Buettner F.F.R., Hartmann M., Grove M., Langereis M.A., de Groot R.J., and Mühlenhoff M. (2015) 9-O-Acetylation of sialic acids is catalysed by CASD1 via a covalent acetyl-enzyme intermediate. Nature Communications, 6:7673 doi: 10.1038/ncomm8673

 

Rebirth Newsletter (03/2015, pp.5-6)

 

Schulz, E.C., Bergfeld, A.K., Ficner, R., and Mühlenhoff, M. (2011). Crystal structure analysis of the polysialic acid specific O-acetyltransferase NeuO. PLoS ONE, 6, e17403.

 

Bergfeld, A.K, Claus, H., Lorenzen, N.K., Spielmann, F., Vogel, U., and Mühlenhoff, M. (2009). The polysialic acid specific O-acetyltransferase OatC from Neisseria meningitidis serogroup C evolved apart from other bacterial sialate:O-acetyltransferases. J. Biol. Chem. 284, 6-16.

 

Bergfeld, A. K., Claus, H., Vogel, U., and Mühlenhoff, M. (2007). Biochemical characterization of the polysialic acid specific O-acetyltransferase NeuO of Escherichia coli K1. J. Biol. Chem. 282, 22217-22227.

 

 

 

Publications

 

(1) Edvardson, S., Baumann, AM., Mühlenhoff, M., Stephan, O., Kuß, A., Shaag, A., He, L., Zenvirt, S., Gerardy-Schahn, R., and Elpeleg, O. (2013) West syndrome caused by ST3GAL-III deficiency. EPILEPSIA 2013 Feb;54(2):e24-7. doi: 10.1111/epi.12050. 

 

(2) Vogt, J., Glumm, R., Schlüter, L., Schmitz, D., Rost, B.R., Streu, N., Rister, B., Suman Bharathi, B., Gagiannis, D., Hildebrandt, H., Weinhold, B., Mühlenhoff, M., Naumann, T., Savaskan, N.E., Brauer, A.U., Reutter, W., Heimrich, B., Nitsch, R., and Horstkorte, R. (2011). Homeostatic regulation of NCAM polysialylation is critical for correct synaptic targeting. Cell. Mol. Life Sci. in press (DOI: 10.1007/s00018-011-0868-2).

 

(3) Eggers, K., Werneburg, S., Schertzinger, A., Abeln, M., Schiff, M., Scharenberg, M.A., Burkhardt, H., Mühlenhoff, M., and Hildebrandt, H. (2011). Polysialic acid controls NCAM signals at cell-cell contacts to regulate focal adhesion independent from FGF receptor activity. J. Cell. Sci.,124, 3279-3291.

 

(4) Hu, H., Eggers, K., Chen, W., Garshasbi, M., Motazacker, M.M., Wrogemann, K., Kahrizi, K., Tzschach, A., Hosseini, M., Bahman, I., Hucho, T., Mühlenhoff, M., Gerardy-Schahn, R., Najmabadi, H., Ropers, H.H., and Kuss, A.W. (2011). ST3GAL3 mutations impair the development of higher cognitive functions. Am. J. Hum. Genet., 89, 407-14.

 

(5) Valentiner, U., Mühlenhoff, M., Lehmann, U., Hildebrandt, H., and Schumacher, U. (2011). Expression of the neural cell adhesion molecule and polysialic acid in human neuroblastoma cell lines. Int. J. Oncol., 39, 417-424.

 

(6) Ahrens, J., Foadi, N., Eberhardt, A., Haeseler, G., Dengler, R., Leffler, A., Mühlenhoff, M., Gerardy-Schahn, R., and Leuwer, M. (2011). Defective polysialylation and sialylation induce opposite effects on gating of the skeletal Na+ channel NaV1.4 in chinese hamster ovary cells. Pharmacology, 87, 311–317.

 

(7) Schulz, E.C., Bergfeld, A.K., Ficner, R., and Mühlenhoff, M. (2011). Crystal structure analysis of the polysialic acid specific O-acetyltransferase NeuO. PLoS ONE, 6, e17403.

 

(8) Haastert-Talini, K., Schaper-Rinkel, J., Schmitte, R., Bastian, R., Mühlenhoff, M., Schwarzer, D., Draeger, G., Su, Y., Scheper, T., Gerardy-Schahn, R., Grothe, C. (2010). In vivo evaluation of polysialic acid as part of tissue-engineered nerve transplants. Tissue Eng. Part A, 16, 3085-3098.

 

(9) Galuska, S.P., Rollenhagen, M., Kaup, M., Eggers, K., Oltmann-Norden, I., Schiff, M., Hartmann, M., Weinhold, B., Hildebrandt, H., Geyer, R., Mühlenhoff, M.*, and Geyer H. (2010). Synaptic cell adhesion molecule SynCAM 1 is a target for polysialylation in postnatal mouse brain. Proc. Natl. Acad. Sci. USA, 107, 10250-10255.

*equally contributing last and co-corresponding author

 

(10) Galuska, S.P., Geyer, H., Bleckmann, C., Röhrich, R.C., Maass, K., Bergfeld, A.K., Mühlenhoff, M., and Geyer, R. (2010). Mass spectrometric fragmentation analysis of oligosialic and polysialic acids. Anal. Chem. 82, 2059-2066.

 

(11) Schulz, E.C., Dickmanns, A., Urlaub, H., Schmitt, A., Mühlenhoff, M., Stummeyer, K., Schwarzer, D., Gerardy-Schahn, R., and Ficner, R. (2010). Crystal structure of an intramolecular chaperone mediating triple-beta-helix folding. Nat. Struct. Mol. Biol., 17, 210-205.

 

(12) Schulz, E.C., Schwarzer, D., Frank, M., Stummeyer, K., Mühlenhoff, M., Dickmanns, A., Gerardy-Schahn, R., and Ficner, R. (2010). Structural basis for the recognition and cleavage of polysialic acid by the bacteriophage K1F tailspike protein endoNF. J. Mol. Biol., 397, 341-351.

 

(13) Mordhorst, I.L., Claus, H., Ewers, C., Lappann, M., Schoen, C., Elias, J., Batzilla, J., Dobrindt, U., Wieler, L.H., Bergfeld, A.K., Mühlenhoff, M., and Vogel, U. (2009). O-acetyltranferase gene neuO is segregated according to phylogenetic background and contributes to environmental desiccation resistance in Escherichia coli K1. Environ. Microbiol., 11, 3154-3165.

 

(14) Hildebrandt, H., Mühlenhoff, M., Oltmann-Norden, I., Röckle, I., Burkhardt, H., Weinhold, B., and Gerardy-Schahn, R. (2009). Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity. Brain, 132, 2831-2838.

 

(15) Klehr, M., Koehl, U., Mühlenhoff, M., Tawadros, S., Fischer, T., Schomäcker, K., Heuckmann, J.M., Bochennek, K., and Jensen, M. (2009). The novel chimeric anti-NCAM (neural cell adhesion molecule) antibody ch.MK1 displays antitumor activity in SCID mice but does not activate complement-dependent cytolysis (CDC). J. Immunother. 32, 442-451.

 

(16) Schwarzer, D., Stummeyer, K., Haselhorst, T., Freiberger, F., Rode, B., Grove, M., Scheper, T., von Itzstein, M., Mühlenhoff, M., and Gerardy-Schahn, R. (2009). Proteolytic release of the intramolecular chaperone domain confers processivity to endosialidase F. J. Biol. Chem. 284, 9465-9474.

 

(17) Claus, H., Stummeyer, K., Batzilla, J., Mühlenhoff, M., and Vogel, U. (2009). Amino acid 310 determines the donor substrate specificity of serogroup W-135 and Y capsule polymerases of Neisseria meningitides. Mol. Microbiol. 71, 960-971.

 

(18) Bergfeld, A.K, Claus, H., Lorenzen, N.K., Spielmann, F., Vogel, U., and Mühlenhoff, M. (2009). The polysialic acid specific O-acetyltransferase OatC from Neisseria meningitidis serogroup C evolved apart from other bacterial sialate:O-acetyltransferases. J. Biol. Chem. 284, 6-16.

 

(19) Rode, B., Endres, C., Ran, C., Stahl, F., Beutel, S., Kasper, C., Galuska, S., Geyer, R., Mühlenhoff, M., Gerardy-Schahn, R., Scheper, T. (2008). Large-scale production and homogenous purification of long chain polysialic acids from E. coli K1. J. Biotechnol., 135, 202-209.

 

(20) Röckle, I., Seidenfaden, R., Weinhold, B., Mühlenhoff, M., Gerardy-Schahn, R., and Hildebrandt, H. (2008). Polysialic acid controls NCAM-induced differentiation of neuronal precursors into calretinin-positive olfactory bulb interneurons. Dev. Neurobiol. 68, 1170-1184.

 

(21) Pekcec, A., Fuest, Ch., Mühlenhoff, M., Gerardy-Schahn, R., and Potschka, H. (2008). Targeting epileptogenesis-associated induction of neurogenesis by enzymatic depolysialylation of NCAM counteracts spatial learning dysfunction but fails to impact epilepsy development. J. Neurochem. 105, 389-400.

 

(22) Schreiber, S.C., Giehl, K., Kastilan, C., Hasel, C., Mühlenhoff, M., Adler, G., Wedlich, D., and Menke, A. (2008). Polysialylated NCAM represses E-cadherin-mediated cell-cell adhesion in pancreatic tumor cells. Gastroenterology, 134, 1555-1566.

 

(23) Oltmann-Norden, I., Galuska, S.P., Hildebrandt, H., Geyer, R., Gerardy-Schahn, R., Geyer, H., and Mühlenhoff, M. (2008). Impact of the polysialyltransferases ST8SiaII and ST8SiaIV on polysialic acid synthesis during postnatal mouse brain development. J. Biol. Chem. 283, 1463-71.

 

(24) Galuska, S.P., Geyer, R., Gerardy-Schahn, R., Mühlenhoff, M., and Geyer, H. (2008). Enzyme-dependent variations in the polysialylation of the neural cell adhesion molecule NCAM in vivo. J. Biol. Chem. 283, 17-28.

 

(25) Galuska, S.P., Geyer, R., Mühlenhoff, M., and Geyer, H. (2007). Characterization of Oligo- and Polysialic Acids by MALDI-TOF-MS. Anal. Chem. 79, 7161-7169.

 

(26) Freiberger, F., Claus, H., Günzel, A., Oltmann-Norden, I., Vionnet, J., Mühlenhoff, M., Vogel, U., Vann, W.F., Gerardy-Schahn, R., and Stummeyer, K. (2007). Biochemical characterization of a Neisseria meningitidis polysialyltransferase reveals novel functional motifs in bacterial sialyltransferases. Mol. Microbiol. 65, 1258-75.

 

(27) Leiman, P.G., Battisti, A.J., Bowman, V.D., Stummeyer, K., Mühlenhoff, M., Gerardy-Schahn, R., Scholl, D., and Molineux, I.J. (2007). The Structures of Bacteriophages K1E and K1-5 Explain Processive Degradation of Polysaccharide Capsules and Evolution of New Host Specificities. J. Mol. Biol. 371, 836-849.

 

(28) Bergfeld, A. K., Claus, H., Vogel, U., and Mühlenhoff, M. (2007). Biochemical characterization of the polysialic acid specific O-acetyltransferase NeuO of Escherichia coli K1. J. Biol. Chem. 282, 22217-22227.

 

(29) Jensen, M., Klehr, M., Vogel, A., Schmitz, S., Tawadros, S., Mühlenhoff, M., Pluck, A., Fischer, T., Schomacker, K., Schultze, J. L., and Berthold, F. (2007). One step generation of fully chimeric antibodies using Cgamma1- and Ckappa mutant mice. J. Immunother. 30, 338-349.

 

(30) Pekcec, A., Mühlenhoff, M., Gerardy-Schahn, R., and Potschka, H. (2007). Impact of the PSA-NCAM system on pathophysiology in a chronic rodent model of temporal lobe epilepsy. Neurobiol. Dis. 27, 54-66.

 

(31) Schwarzer, D., Stummeyer, K., Gerardy-Schahn, R., and Mühlenhoff, M. (2007). Characterization of a novel intra-molecular chaperone domain conserved in endosialidases and other bacteriophage tail spike and fiber proteins. J. Biol. Chem. 282, 2821-2831.

 

(32) Haselhorst, T., Stummeyer, K., Mühlenhoff, M., Schaper, W., Gerardy-Schahn, R., and von Itzstein M. (2006). Endosialidase NF Appears To Bind PolySia DP5 in a Helical Conformation. Chembiochem. 7, 1875-1877.

 

(33) Galuska, S. P., Oltmann-Norden, I., Geyer, H., Weinhold, B., Kuchelmeister, K., Hildebrandt, H., Gerardy-Schahn, R., Geyer, R., and Mühlenhoff, M. (2006). Polysialic acid profiles of mice expressing variant allelic combinations of the polysialyltransferases ST8SiaII and ST8SiaIV. J. Biol. Chem. 281, 31605-31615.

 

(34) Stummeyer, K., Schwarzer, D., Claus, H., Vogel, U., Gerardy-Schahn, R., and Mühlenhoff, M. (2006). Evolution of bacteriophages infecting encapsulated bacteria: lessons from Eschericha coli K1 specific bacteriophages. Mol. Microbiol. 60, 1123-1135.

 

(35) Weinhold, B., Seidenfaden, R., Röckle, I., Mühlenhoff, M., Schertzinger, F., Conzelmann, S., Marth, J. D., Gerardy-Schahn, R., and Hildebrandt, H. (2005). Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule. J. Biol. Chem. 280, 42971-42977.

 

(36) Stummeyer, K., Dickmanns A., Mühlenhoff, M., Gerardy-Schahn, R., and Ficner, R. (2005). Crystal structure of the polysialic acid-degrading endosialidase of bacteriophage K1F. Nat. Struct. Mol. Biol. 12, 90-96.

 

(37) Horstkorte, R. Mühlenhoff, M., Reutter, W., Nöhring, S., Zimmermann-Kordmann, M., and Gerardy-Schahn, R. (2004). Selective inhibition of polysialyltransferase ST8SiaII by unnatural sialic acids. Exp. Cell Res. 298, 268-274.

 

(38) Mühlenhoff, M., Stummeyer, K., Grove, M., Sauerborn, M., and Gerardy-Schahn, R. (2003). Proteolytic cleavage and oligomerization of bacteriophage-derived endosialidases. J. Biol. Chem. 278, 12634-12644.

 

(39) Häyrinen, J., Haseley, S., Talaga, P., Mühlenhoff, M., Finne, J., Vliegenthart, J.F.G. (2002). High affinity binding of long-chain polysialic acid to antibody, and modulation by divalent cations and polyamines. Mol. Immunol. 39, 399-411.

 

(40) Münster, A.-K., Weinhold, B., Gotza, B., Mühlenhoff, M., Frosch, M. and Gerardy-Schahn, R. (2002). Nuclear localization signal of murine CMP-Neu5Ac synthetase includes residues required for both nuclear targeting and enzymatic acitivity. J. Biol. Chem. 277, 19688-19696.

 

(41) von der Ohe, M., Wheeler, S.F., Wuhrer, M., Harvey, D.J., Liedtke, S., Mühlenhoff, M., Gerardy-Schahn, R., Geyer, H., Dwek, R.A., Geyer, R., Wing, D.R., and Schachner, M. (2002). Localization and characterization of polysialic acid-containing N-linked glycans from bovine NCAM. Glycobiology 12, 47-63.

 

(42) Mühlenhoff, M., Manegold, A., Windfuhr, M., Gotza, B and Gerardy-Schahn, R. (2001). The impact of N-glycosylation on the functions of polysialyltransferases. J. Biol. Chem. 276, 34066-34073.

 

(43) Windfuhr, M., Manegold, A., Mühlenhoff, M., Eckhardt, M., and Gerardy-Schahn, R. (2000). Molecular defects that cause loss of polysialic acid in the complementation group 2A10. J. Biol. Chem. 275, 32861-32870.

 

(44) Münster, A.-K., Eckhardt, M., Potvin, B., Mühlenhoff, M., Stanley, P., and Gerardy-Schahn, R. (1998). Mammalian cytidine 5'-monophosphate N-acetylneuraminic acid synthetase: a nuclear protein with evolutionarily conserved structural motifs. Proc. Natl. Acad. Sci. USA 95, 9140-9145.

 

(45) Claus, H., Vogel, U., Mühlenhoff, M., Gerardy-Schahn, R., and Frosch, M. (1997). Molecular divergence of the sia locus in different serogroups of Neisseria meningitidis expressing polysialic acid capsules. Mol. Gen. Genet. 257, 28-34.

 

(46) Hammerschmidt, S., Müller, A., Sillmann, H., Mühlenhoff, M., Borrow, R., Fox, A., van Putten, J., Zollinger,W. D., Gerardy-Schahn, R., and Frosch, M. (1996). Capsule phase variation in Neisseria meningitidis serogroup B by slipped-strand mispairing in the polysialyltransferase gene (siaD): correlation with bacterial invasion and the outbreak of meningococcal disease. Mol. Microbiol. 20, 1211-1220.

 

(47) Eckhardt, M., Mühlenhoff, M., Bethe, A., and Gerardy-Schahn, R. (1996). Expression cloning of the Golgi CMP-sialic acid transporter. Proc. Natl. Acad. Sci. USA 93, 7572-7576.

 

(48) Mühlenhoff, M., Eckhardt, M., Bethe, A., Frosch, M., and Gerardy-Schahn, R. (1996). Autocatalytic polysialylation of polysialyltransferase-1. EMBO J. 15, 6943-6950.

 

(49) Mühlenhoff, M., Eckhardt, M., Bethe, A., Frosch, M., and Gerardy-Schahn, R. (1996). Polysialylation of NCAM by a single enzyme. Curr. Biol. 6, 1188-1191.

 

(50) Gerardy-Schahn, R., Bethe, A., Brennecke, T., Mühlenhoff, M., Eckhardt, M., Ziesing, S., Lottspeich, F., and Frosch, M. (1995). Molecular cloning and functional expression of bacteriophage PK1E- encoded endoneuraminidase Endo NE. Mol. Microbiol. 16, 441-450.

 

(51) Eckhardt, M., Mühlenhoff, M., Bethe, A., Koopman, J., Frosch, M., and Gerardy-Schahn, R. (1995). Molecular characterization of eukaryotic polysialyltransferase-1. Nature 373, 715-718.

 

 

Reviews

 

(1) Hildebrandt, H., Mühlenhoff, M., and Gerardy-Schahn, R., (2010). Polysialylation of NCAM. Adv. Exp. Med. Biol., 663, 95-109.

 

(2) Mühlenhoff, M., Oltmann-Norden I., Weinhold, B., Hildebrandt, H., and Gerardy Schahn, R. (2009). Brain development needs sugar: the role of polysialic acid in steering NCAM functions. Biol. Chem., 390, 567-574.

 

(3) Hildebrandt, H., Mühlenhoff, M., Weinhold, B., and Gerardy-Schahn, R., (2007). Dissecting polysialic acid and NCAM functions in brain development. J. Neurochem 103 (Suppl.1), 56-64.

 

(4) Mühlenhoff, M., Eckhardt, M., and Gerardy-Schahn, R. (1998). Polysialic acid: three-dimensional structure, biosynthesis and function. Curr. Opin. Struct. Biol. 8, 558-564.