The Sec14 Homology Module of Neurofibromin Binds Cellular Glycerophospholipids: Mass Spectrometry and Structure of a Lipid Complex

Welti, Stefan; Fraterman, Sven; D’Angelo, I.; Wilm, Matthias; Scheffzek, Klaus

doi:10.1016/j.jmb.2006.11.055

Cited by 68 publications

(74 citation statements)

References 69 publications

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“…Cloning, Expression and purification of HsNF1 Sec14-PH and variants: The Sec14-PH region (residues 1545-1816) of human neurofibromin (Bonneau, et al, 2004;D'Angelo, et al, 2006;Welti, et al, 2007) was amplified from cDNA by PCR and cloned (Sambrook and Russell, 2001) into the pETM11 expression vector (EMBL, protein expression and purification core facility). All deletion and point mutations were made by using the Quickchange site-directed mutagenesis kit (Stratagene) following manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…After an ultracentrifugation step (40.000 rpm, 1 h , 277K), the cell lysate was continuously applied to a pre-equilibrated 1 ml HisTrap column (GE healthcare) in a circulatory way for 2 h and washed with 10 ml buffer LyB. Following 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Liposome preparation, lipid exchange assay and mass spectrometry: The preparation of liposomes, lipid exchange assays and extraction of lipids from protein samples for MS analysis was done as previously described (Welti, et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

“…While numerous binding partners of neurofibromin have been reported (Patrakitkomjorn, et al, 2008;Phan, et al, 2010;Welti, et al, 2008), the physiological significance of the underlying protein-protein Welti, et al, 2007). A number of missense mutations of the Sec14-PH module have been identified in NF1-patients as well as single and double amino acid deletions (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin

et al. 2011

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin

et al. 2011

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“…68 The biological role of the Sec14 domain is still unclear, but its yeast homolog Sec14p is implicated in protein and lipid trafficking, 69 and Sec14-like domains have been found in a number of mammalian lipidbinding proteins. 70 In recent follow-up studies, several glycerophospholipids, in particular phosphatidylethanolamine and phosphatidylglycerol, were found to interact with the Sec14 domain. 70 Thus, the Sec14 module could facilitate NF1 interaction with glycerophospholipids in certain compartments to selectively regulate distinct Ras signaling pathways.…”

Section: Nf1mentioning

confidence: 99%

“…70 In recent follow-up studies, several glycerophospholipids, in particular phosphatidylethanolamine and phosphatidylglycerol, were found to interact with the Sec14 domain. 70 Thus, the Sec14 module could facilitate NF1 interaction with glycerophospholipids in certain compartments to selectively regulate distinct Ras signaling pathways.…”

Section: Nf1mentioning

confidence: 99%

Differential Regulation of RasGAPs in Cancer

et al. 2011

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Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell-and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.

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Novel association of neurofibromatosis type 1‐causing mutations in families with neurofibromatosis‐noonan syndrome

Ekvall

Sjörs

Jonzon

et al. 2013

American J of Med Genetics Pt A

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Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.

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The Sec14 Homology Module of Neurofibromin Binds Cellular Glycerophospholipids: Mass Spectrometry and Structure of a Lipid Complex

Cited by 68 publications

References 69 publications

Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin

Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin

Differential Regulation of RasGAPs in Cancer

Novel association of neurofibromatosis type 1‐causing mutations in families with neurofibromatosis‐noonan syndrome

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