The folding and structural integrity of the first LIN-12 module of human Notch1 are calcium-dependent - PubMed (original) (raw)
. 1999 Apr 13;38(15):4736-42.
doi: 10.1021/bi982713o.
Affiliations
- PMID: 10200161
- DOI: 10.1021/bi982713o
The folding and structural integrity of the first LIN-12 module of human Notch1 are calcium-dependent
J C Aster et al. Biochemistry. 1999.
Abstract
Notch1 is a member of a conserved family of large modular type 1 transmembrane receptors that control differentiation in multicellular animals. Notch function is mediated through a novel signal transduction pathway involving successive ligand-induced proteolytic cleavages that serve to release the intracellular domain of Notch, which then translocates to the nucleus and activates downstream transcription factors. The extracellular domain of all Notch receptors have three iterated LIN-12 modules that appear to act as negative regulatory domains, possibly by limiting proteolysis. Each LIN-12 module contains three disulfide bonds and three conserved aspartate (D) or asparagine (N) residues. To begin to understand the structural basis for LIN-12 function, the first LIN-12 module of human Notch1 (rLIN-12.1) has been expressed recombinantly in Escherichia coli and purified in a reduced form. In redox buffers, rLIN-12.1 forms only one disulfide isomer in the presence of millimolar Ca2+ concentrations, whereas multiple disulfide isomers are observed in the presence of Mg2+ and EDTA. Further, mutation of conserved residues N1460, D1475, and D1478 to alanine abolishes Ca2+-dependent folding of this module. Mass spectrometric analysis of partially reduced rLIN-12.1 has been used to deduce that disulfide bonds are formed between the first and fifth (C1449-C1472), second and fourth (C1454-C1467), and third and sixth (C1463-C1479) cysteines of this prototype module. This arrangement is distinct from that observed in other modules, such as EGF and LDL-A, that also contain three disulfide bonds. One-dimensional proton nuclear magnetic resonance shows that Ca2+ induces a dramatic increase in the extent of chemical shift dispersion of the native rLIN-12.1 amide protons, as seen for the Ca2+-binding LDL-A modules. We conclude that Ca2+ is required both for proper folding and for the maintenance of the structural integrity of Notch/LIN-12 modules.
Similar articles
- Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1.
Vardar D, North CL, Sanchez-Irizarry C, Aster JC, Blacklow SC. Vardar D, et al. Biochemistry. 2003 Jun 17;42(23):7061-7. doi: 10.1021/bi034156y. Biochemistry. 2003. PMID: 12795601 - Folding, calcium binding, and structural characterization of a concatemer of the first and second ligand-binding modules of the low-density lipoprotein receptor.
Bieri S, Atkins AR, Lee HT, Winzor DJ, Smith R, Kroon PA. Bieri S, et al. Biochemistry. 1998 Aug 4;37(31):10994-1002. doi: 10.1021/bi980452c. Biochemistry. 1998. PMID: 9692993 - Structural independence of ligand-binding modules five and six of the LDL receptor.
North CL, Blacklow SC. North CL, et al. Biochemistry. 1999 Mar 30;38(13):3926-35. doi: 10.1021/bi9821622. Biochemistry. 1999. PMID: 10194304 - Notch/LIN-12 signaling: transduction by regulated protein slicing.
Kimble J, Henderson S, Crittenden S. Kimble J, et al. Trends Biochem Sci. 1998 Sep;23(9):353-7. doi: 10.1016/s0968-0004(98)01263-8. Trends Biochem Sci. 1998. PMID: 9787642 Review. - Structure/function studies of lin-12/Notch proteins.
Greenwald I. Greenwald I. Curr Opin Genet Dev. 1994 Aug;4(4):556-62. doi: 10.1016/0959-437x(94)90072-b. Curr Opin Genet Dev. 1994. PMID: 7950324 Review.
Cited by
- Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond.
Pozzo F, Bittolo T, Tissino E, Zucchetto A, Bomben R, Polcik L, Dannewitz Prosseda S, Hartmann TN, Gattei V. Pozzo F, et al. Cancers (Basel). 2022 Jun 17;14(12):2997. doi: 10.3390/cancers14122997. Cancers (Basel). 2022. PMID: 35740661 Free PMC article. Review. - Analysis of the Conditions That Affect the Selective Processing of Endogenous Notch1 by ADAM10 and ADAM17.
Alabi RO, Lora J, Celen AB, Maretzky T, Blobel CP. Alabi RO, et al. Int J Mol Sci. 2021 Feb 12;22(4):1846. doi: 10.3390/ijms22041846. Int J Mol Sci. 2021. PMID: 33673337 Free PMC article. - Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure-function studies in Drosophila.
Yamamoto S. Yamamoto S. Dev Growth Differ. 2020 Jan;62(1):15-34. doi: 10.1111/dgd.12640. Epub 2020 Jan 13. Dev Growth Differ. 2020. PMID: 31943162 Free PMC article. Review. - Notch signaling in breast cancer: From pathway analysis to therapy.
Krishna BM, Jana S, Singhal J, Horne D, Awasthi S, Salgia R, Singhal SS. Krishna BM, et al. Cancer Lett. 2019 Oct 1;461:123-131. doi: 10.1016/j.canlet.2019.07.012. Epub 2019 Jul 18. Cancer Lett. 2019. PMID: 31326555 Free PMC article. Review. - High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation.
Rehman M, Vodret S, Braga L, Guarnaccia C, Celsi F, Rossetti G, Martinelli V, Battini T, Long C, Vukusic K, Kocijan T, Collesi C, Ring N, Skoko N, Giacca M, Del Sal G, Confalonieri M, Raspa M, Marcello A, Myers MP, Crovella S, Carloni P, Zacchigna S. Rehman M, et al. JCI Insight. 2019 Apr 18;4(8):e123987. doi: 10.1172/jci.insight.123987. eCollection 2019 Apr 18. JCI Insight. 2019. PMID: 30996132 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous