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Traffic in Human Genetic Diseases


Sec23a has been implicated in a rare craniofacial disorder (CLSD) that causes various skeletal defects. The CLSD mutation maps to a residue on the surface of Sec23a that is away from contact with the membrane. Although the mutation, F382L, produces a conservative substitution, the effect of the allele on primary fibroblasts cultured from patients is profound, with a substantial distortion of the ER reminiscent of the original and lethal sec23-1 of yeast. Humans have two paralogs of Sec23 (a and b), but cultured fibroblasts and calvarial osteoblasts, which may be responsible for the skeletal effects in CLSD patients, express only one copy, Sec23a. We have established a vesicle-budding reaction reconstituted with mammalian COPII proteins and ER membranes to explore CLSD and other unique features of human membrane protein traffic. Using pure recombinant proteins, we found that the CLSD mutation interferes with the binding and assembly of a scaffold complex, Sec13/31, which normally builds upon the inner coat of Sar1p and Sec23/24p.


Sec24 is responsible for membrane cargo protein sorting into COPII vesicles. Mammals have four Sec24 paralogs, each of which may be responsible for the recognition of different cohorts of cargo proteins. One dramatic example has been elucidated in collaboration with David Ginty's lab (HHMI, Johns Hopkins University School of Medicine). Ginty's lab has characterized a chain-terminating mutation early in the mouse gene encoding Sec24b that turned up in a screen for mutants defective in neural tube closure. In collaboration with Ginty, we have discovered that a signaling receptor, Vangl2, required in the establishment of planar polarity in the neural epithelium, fails to be trafficked in the Sec24b mutant. Thus, Sec24b appears to be responsible for an unusually restricted range of cargo molecules, none of which are essential until fairly late in embryonic development. Other paralogs of Sec24 may display quite different roles in development and physiologic function.

Immunofluorescence staining of anti-HA (green) and anti-PDI (red) in COS7 cells. Transiently transfected wild-type HA–Vangl2 reached the cell surface, while both Vangl2 mutants Vangl2(D255E) and Vangl2(S464N) remained in the ER where they colocalized with the PDI ER marker.
(From Merte etal (2010), Nature Cell Biology 12, 41 - 46)

Membrane proteins implicated in familial forms of Alzheimer's disease (FAD) are substrates for vesicular trafficking, and defects associated with protein transport may play a role in the pathology of AD. Presenilin 1 (PS1) is an essential subunit of an enzyme, gamma-secretase, that serves important roles in the maturation of proteins involved in signaling and development. However, mutant forms of PS1 cause unscheduled processing of amyloid precursor protein (APP) to generate an amyloidogenic peptide that accumulates in brain neuritic plaques that are characteristic of AD. Surprisingly, the PS1 mutations that potentiate the action of gamma-secretase on APP are spread throughout the molecule, including in domains exposed to the cytoplasm, to the lumen of the ER or extracellular space, and within the membrane bilayer. These alleles may produce forms of PS1 that fold improperly and retard the traffic of gamma-secretase. Such impaired traffic could influence the transport and proteolytic processing of APP. Our current work is focused on the role of the early endosome as a station for aberrant processing of APP.


Vesicle Transport Early in the Secretory Pathway

Vesicle Traffic Late in the Secretory Pathway

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