Scheffzek Klaus, Univ.Prof. Dr.rer.nat

University / Clinic: Medical University Innsbruck
Institute: Biocenter: Division Biological Chemistry
 
Research Area: Signal transduction, structural biology/biochemistry, cellular neurobiology

Email: Klaus.Scheffzek@i-med.ac.at
Web: biocenter.i-med.ac.at/division-of-biological-chemistry

  Funded by: FWF

Research Topic:
Neurofibromatosis type 1 (NF1) is a common genetic disease that affects 1 in 3500 newborns. Patients have an increased risk to develop the disease typical neurofibroma, benign and malignant tumors of the nervous system and display additional hallmarks including pigmentation anomalies, bone deformations and learning disabilities. The tumor suppressor gene NF1 encodes the giant signal regulator neurofibromin (320 kDa) that is not functional in patients due to gene alterations. Neurofibromin is a Ras specific GTPase activating protein (RasGAP) that uses a central GAP domain to down regulate the biological activity of the small G protein Ras that is catalytically mutated in 30% of human malignancies rendering Ras insensitive to the action RasGAPs. We have defined earlier the structural basis for GTPase activation and its loss in oncogenic Ras mutants (Scheffzek et al., 1997). However, the GAP domain accounts for less than 10% of the coding sequence raising the question what the functions of the remaining parts of neurofibromin are.
Our group has a longstanding interest in defining the functional spectrum of neurofibromin in as much detail as possible. A major mission in that context is to define protein interaction partners of neurofibromin, determine the 3-dimensional structures of respective complexes and analyze the impact of individual residues employing protein protein interaction analyses complemented by functional cellular studies. Using structural biology approaches we have previously discovered a bipartite glycerophospholipid binding module composed of an N-terminal Sec14- and a C-terminal PH-like domain (D`Angelo et al., 2006; Welti et al., 2007; Welti et al., 2011). The cellular function of this module that is located at the C-terminal end of the GAP domain is currently unclear.


Project:
  Disease cross talk at the Ras-MAPK pathway, defining the interaction of neurofibromin with Spred proteins.
details ...

Selected publications:
 
  Naschberger A, Fürnrohr B, Lenac Rovis T, Malic S, Scheffzek K, Dieplinger H, Rupp B
The N14 anti-afamin antibody Fab: a rare VL1 CDR glycosylation, crystallographic re-sequencing, molecular plasticity and conservative versus enthusiastic modelling
Acta Crystallogr D Struct Biol. 2016 Dec 1;72(Pt 12):1267-1280.

  Dunzendorfer-Matt T, Mercado E, Maly K, McCormick F, Scheffzek K
The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation
Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7497-502. doi: 10.1073/pnas.1607298113.

  Naschberger A, Fürnrohr BG, Dunzendorfer-Matt T, Bonagura CA, Wright D, Scheffzek K, Rupp B
Cleaning protocols for crystallization robots: preventing protease contamination.
Acta Crystallogr F Struct Biol Commun. 2015 Jan 1;71(Pt 1):100-2. doi: 10.1107/S2053230X14026053.