Functions of the SAR1B protein

SAR1 is a well-known GTPase (guanine tri-phosphatase) which belongs to the ARF (ADP-ribosylation factor) family of small GTPases [34, 35]. SAR1 initiates the assembly of COPII (coat protein complex II) in the endoplasmic reticulum (ER) by binding to SEC12. Then, SAR1-GDP is converted into SAR1-GTP which undergoes a large conformational change in the two switch regions. The residue Threonine 56, in switch 1, forms bonds to the y phosphate and Mg2+ and the residue Glycine 78, in switch 2, binds to the y phosphate. The movements expose the amino terminal, amphipatic a1 helix (« the membrane anchor »>) which then inserts into the ER membrane [36]. Mg2+ has an important regulatory role in this conformational change, mostly related to switch 1 [37]. The membrane-bound SAR1 recruits SEC23-SEC24 and triggers the formation of the pre-budding complex which then recruits SEC13-SEC31 to form the COPII vesicle [36, 38]. SEC24 interacts with specific cargo proteins and concentrates them into the COPII vesicle [39]. SAR1 GTP hydrolysis is stimulated by SEC23 and SEC31 and permits vesicle fission, allowing transport to the Golgi, and eventual disassembly of the coat for recycling of the components [40-42]. SED4p, a protein with 45% homology to SEC12p, accelerates the dissociation of SEC23-24 from the membrane if no cargo is transported with COPII vesicles and it has been proposed that this restricted disassembly might play a role in concentrating cargoes into COPII vesicles [43].

The typical size of the COPII vesicles ranges from 60 to 70 nm in diameter, which would appear to prohibit these vesicles from carrying chylomicrons (250 nm average diameter) from the ER to the Golgi apparatus [44]. Another vesicle (350-500 nm in diameter), the pre-chylomicron transport vesicle (PCTV), has been shown to be able to transport chylomicrons [45]. The PCTV is composed of several proteins: VAMP7 (vesicle-associated membrane protein 7) which is the v-SNARE (vesicle-associated soluble N-ethylmaleimide-sensitive factor attachment protein receptor), apoprotein B48 (a cargo), FABP1 (also called liver fatty acid- binding protein, LFABP) (budding initiator), the fatty acid transporter CD36 (a fatty

Electron microscopy of duodenal biopsies of patients with AD. As shown for AD3 (A, B, C) and AD2 (D, E), two types of particles are apparent in the enterocytes in these patients (A, D): large lipid droplets, free in the cytoplasm (L), and smaller, lipoprotein-sized like particles (Lp), surrounded by a membrane. A higher magnification shows in (B) some individual lipoprotein-sized particles surrounded by a membrane (*)near a Golgi apparatus (G) which appears distended but devoid of particles and in (C, E) numerous lipoprotein-sized particles accumulated in membrane bound compartment (membrane, white arrow). The intercellular spaces are empty. The cell nucleus is labelled N.

Figure 2. Electron microscopy of duodenal biopsies of patients with AD (from A. Georges ref 27)

SAR1 S.c.---MAGWDIFGWFRDVLASLGLWNKHGKLLFJUGLDNAGi TTLLHNUKNDR47

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