Premium
Examining the Impact of Point Mutations L1569H and L1663T on the Stability and the Secondary Structure of the Human Notch 2 Heterodimerization Region
Author(s) -
Schoppa Isabelle,
Kim Stephanie
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.889.6
Subject(s) - notch signaling pathway , transmembrane domain , point mutation , biology , transmembrane protein , microbiology and biotechnology , notch proteins , receptor , extracellular , mutation , signal transduction , genetics , gene
Notch receptors are transmembrane glycoproteins of a highly conserved signaling pathway that is crucial in regulation of multiple cell differentiation and developmental processes in multicellular organisms. There are four Notch receptors in higher eukaryotic organisms, and aberrant signaling in any of these receptors is associated with many types of diseases. The Notch protein has a modular domain structure consisting of an extracellular domain that contains the ligand binding domain and the negative regulatory region (NRR), and an intracellular domain. The NRR is composed of three tandem LIN‐12/Notch‐Repeats (LNRs) followed by the Heterodimerization (HD) region. Our work focuses on the HD region in Human Notch 2 (hN2). Structural integrity of the NRR plays an integral part in preventing ligand‐independent signaling, and point mutations in the HD region are associated with T‐cell acute lymphoblastic leukemias/lymphomas (T‐ALL) 1 . Previous work from our laboratory showed that two of the more common T‐ALL associated Leu to Pro mutations in the core of the HD region had very different effects on the stability and secondary structure of the NRR. In this work, we examine the impact of two unique T‐ALL associated mutations, L1569H and L1663T. While L1569H is in the hydrophobic core like the mutations previously studied, L1663T is on the interface of the HD and the LNR region, setting it apart from the other T‐ALL associated mutations. Our work will contribute to a global understanding of the relative importance of structural integrity versus stability in T‐ALL cases.