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Pathogenic Mutations Associated with Legius Syndrome Modify the Spred1 Surface and Are Involved in Direct Binding to the Ras Inactivator Neurofibromin.

Abstract：

:Neurofibromatosis type I (NF1) and Legius syndrome are rare inherited disorders that share diagnostic symptoms including dermal abnormalities like axillary and inguinal freckling and café au lait spots. In addition, patients suffering from NF1 have a demanding risk for the development of severe tumors of the peripheral and central nervous system among other NF1-specific symptoms. NF1 and Legius syndrome are caused by alterations in the NF1 and SPRED1 genes encoding the Ras inhibitors neurofibromin and Spred1 (sprouty related EVH1 domain-containing protein), respectively. Neurofibromin functions as a Ras-specific GTPase-activating protein (Ras-GAP), and Spred1 enhances Ras inactivation by recruiting neurofibromin from the cytosol to membrane-anchored Ras. In a previous study, we mapped the Spred binding site to the GAP-related domain of neurofibromin (NF1-GAP) and identified the GAPex subdomain as critical for Spred1 binding. Here, we characterize the binding site of these proteins in more detail focusing on a mutant Spred1 variant carrying a pathogenic missense mutation (threonine 102 to arginine). Introduction of this mutation, which locates at the N-terminal EVH1 domain of Spred1, weakens the interaction with neurofibromin by about 3 orders of magnitude without perturbing the protein fold, and the binding site of NF1-GAP on the mutant Spred1(EVH1) variant can be identified by NMR spectroscopy. Taken together, our data provide structural insight into the interaction of Spred1 and neurofibromin and characterize the structural or functional consequence of selected patient-derived mutations associated with Legius syndrome.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Führer S,Tollinger M,Dunzendorfer-Matt T

doi

10.1016/j.jmb.2019.07.038

subject

Has Abstract

pub_date

2019-09-06 00:00:00

pages

3889-3899

issue

19

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(19)30500-5

journal_volume

431

pub_type

杂志文章

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