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PROSITE documentation PDOC50258
LNR (Lin-12/Notch) repeat profile


Description

The Lin-12/Notch proteins act as transmembrane receptors for intercellular signals that specify cell fates during animal development. In response to ligand, proteolytic cleavages release the intracellular domain of Notch, which then gains access to the nucleus and acts as a transcriptional co-activator [1]. The Lin-12/Notch repeat (LNR) is a region present only in Notch related proteins. The LNR is supposed to negatively regulates the Lin-12/Notch proteins activity, and participates in maintaining the receptor in its resting conformation prior to ligand binding. It is a triplication of an about 35-40 amino acid module present on the extracellular part of the protein [2,3]. Each module contains six cysteine residues engaged in three disulfide bonds and three conserved aspartate and asparagine residues [1]. The biochemical characterization of a recombinantly expressed LIN-12.1 module from the human Notch1 receptor indicates that the disulfide bonds are formed between the first and fifth, second and fourth, and third and sixth cysteines (see the schematic representation below).

                    +------------+
            +-------|------------|----+
            |       |            |    |
            CxxxxxxxCxxxxxxxxCxxxCxxxxCxxxxxxC
                             |               |
                             +---------------+
'C': conserved cysteine involved in a disulfide bond.

The formation of this particular disulfide isomer is favored by the presence of Ca++, which is also required to maintain the structural integrity of the rLIN-12.1 module. The structure of a human LNR has been solved by NMR (see <PDB:1PB5>). It shows that the LNR is composed of two α-helices [4]. The conserved aspartate and asparagine residues are important for Ca++ binding, and thereby contribute to the native fold [1,4].

The profile we developed covers the LNR domain from the first to the last conserved cysteine.

Last update:

January 2006 / First entry.

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Technical section

PROSITE method (with tools and information) covered by this documentation:

LNR, PS50258; LNR (Lin-12/Notch) repeat profile  (MATRIX)


References

1AuthorsAster J.C. Simms W.B. Zavala-Ruiz Z. Patriub V. North C.L. Blacklow S.C.
TitleThe folding and structural integrity of the first LIN-12 module of human Notch1 are calcium-dependent.
SourceBiochemistry 38:4736-4742(1999).
PubMed ID10200161
DOI10.1021/bi982713o

2AuthorsGreenwald I.
TitleLIN-12/Notch signaling: lessons from worms and flies.
SourceGenes Dev. 12:1751-1762(1998).
PubMed ID9637676

3AuthorsGreenwald I.
TitleStructure/function studies of lin-12/Notch proteins.
SourceCurr. Opin. Genet. Dev. 4:556-562(1994).
PubMed ID7950324

4AuthorsVardar D. North C.L. Sanchez-Irizarry C. Aster J.C. Blacklow S.C.
TitleNuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1.
SourceBiochemistry 42:7061-7067(2003).
PubMed ID12795601
DOI10.1021/bi034156y



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