TY  - JOUR
AU  - Fluhrer, Regina
AU  - Martin, Lucas
AU  - Klier, Bärbel
AU  - Haug-Kröper, Martina
AU  - Grammer, Gudula
AU  - Nuscher, Brigitte
AU  - Haass, Christian
TI  - The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b).
JO  - The journal of biological chemistry
VL  - 287
IS  - 7
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.60645
M1  - DZNE-2020-02760
SP  - 5156-5163
PY  - 2012
AB  - Regulated intramembrane proteolysis is a widely accepted concept describing the processing of various transmembrane proteins via ectodomain shedding followed by an intramembrane cleavage. The resulting cleavage products can be involved in reverse signaling. Presenilins, which constitute the active center of the γ-secretase complex, signal peptide peptidase (SPP), and its homologues, the SPP-like (SPPL) proteases are members of the family of intramembrane-cleaving aspartyl proteases of the GXGD-type. We recently demonstrated that Bri2 (itm2b) is a substrate for regulated intramembrane proteolysis by SPPL2a and SPPL2b. Intramembrane cleavage of Bri2 is triggered by an initial shedding event catalyzed by A Disintegrin and Metalloprotease 10 (ADAM10). Additionally primary sequence determinants within the intracellular domain, the transmembrane domain and the luminal juxtamembrane domain are required for efficient cleavage of Bri2 by SPPL2b. Using mutagenesis and circular dichroism spectroscopy we now demonstrate that a high α-helical content of the Bri2 transmembrane domain (TMD) reduces cleavage efficiency of Bri2 by SPPL2b, while the presence of a GXXXG dimerization motif influences the intramembrane cleavage only to a minor extent. Surprisingly, only one of the four conserved intramembrane glycine residues significantly affects the secondary structure of the Bri2 TMD and thereby its intramembrane cleavage. Other glycine residues do not influence the α-helical content of the transmembrane domain nor its intramembrane processing.
KW  - ADAM Proteins: genetics
KW  - ADAM Proteins: metabolism
KW  - ADAM10 Protein
KW  - Amino Acid Motifs
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Circular Dichroism: methods
KW  - HEK293 Cells
KW  - Humans
KW  - Membrane Glycoproteins
KW  - Membrane Proteins: genetics
KW  - Membrane Proteins: metabolism
KW  - Mutagenesis
KW  - Protein Structure, Tertiary
KW  - Proteolysis
KW  - ITM2B protein, human (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - SPPL2b protein, human (NLM Chemicals)
KW  - ADAM Proteins (NLM Chemicals)
KW  - ADAM10 Protein (NLM Chemicals)
KW  - ADAM10 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22194595
C2  - pmc:PMC3281599
DO  - DOI:10.1074/jbc.M111.328104
UR  - https://pub.dzne.de/record/136438
ER  -