Neprilysiini haimasaarekkeessa
Sitaatti:
Knowledge regarding the subcellular localization and
conformational changes of neprilysin may provide clues about its
interaction with hIAPP. At this time, the specific localization of
neprilysin within the islet has not been clearly defined. Previously,
using an immunohistochemical approach, we showed that islet neprilysin
localized to both β-cells and non-β-cells and is largely membranous with
some cytoplasmic localization (8).
Reports describing neprilysin in non-islet tissues also document that
it is predominantly plasma membrane-bound;
however, there is evidence in
neurons that neprilysin is also localized in secretory vesicles (41).
Furthermore, the neprilysin homologue neprilysin 2, which shares many of the same properties as neprilysin (42), exists in the endoplasmic reticulum (43).
Thus, when considering where in the islet neprilysin may be acting to
inhibit hIAPP fibril formation, any of these sites are possible. In line
with its ability to trap peptides via conformational changes at the
plasma membrane (44),
neprilysin could prevent aggregation of hIAPP secreted into the
extracellular space, a site where amyloid deposits commonly occur (18).
Neprilysin in secretory vesicles or the endoplasmic reticulum could
also act to sequester excess hIAPP prior to its release from the β-cell
and thus impede fibril formation. Clearly, more extensive studies are
required to understand any potential neprilysin-hIAPP interactions that
may impact islet amyloid formation.
In summary, we have demonstrated that the enzyme neprilysin impacts islet amyloid formation in vitro.
Neprilysin does not cleave the hIAPP peptide, and therefore reduces
fibril formation via another mechanism. Although enzymatic activity may
not be required, the active site of neprilysin does appear to be
involved and hIAPP fibril formation may be impeded via a protein-protein
interaction with neprilysin.
Importantly, our studies highlight that
amyloidogenesis in the islet can differ markedly from that in the brain,
where neprilysin has been shown to reduce amyloid plaque formation
primarily by cleaving the peptide constituent of Alzheimer's amyloid.
Our findings also have implications for approaches taken in developing
amyloid inhibitors, which could focus on inhibition of IAPP fibril
assembly in addition to IAPP cleavage.
- hIAPP-proteiinista
- saarekkeen hIAPP:n amyloidogeeninen jakso NFGAIL ja FFLVA
- Vert. Abeeta amylodogeeniin jaksoon: KLVFFAE
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