Palmitoylation cycles and regulation of protein function (Review)

Figures & data

Figure 1.  Schematic model of cycling of the Ras and GAD65 proteins between cytosol, ER/Golgi, and PM/SVM. Newly synthesized hydrophilic and soluble protein (green) undergoes an irreversible hydrophobic modification in the cytosol (Step 1). The resulting hydrophobic protein (red) reversibly associates with ER and Golgi membranes, establishing an equilibrium between membrane and cytosolic pools. In Golgi membranes, the protein undergoes palmitoylation (Step 2) catalyzed by a palmitoyl-transferase. The palmitoylated protein (blue) is targeted to the TGN, shifting the equilibrium from ER and toward the Golgi. From the TGN, the protein is targeted to cytosolic vesicles and a pathway to either the PM (Ras) or synaptic vesicles (GAD65). A depalmitoylation along this pathway (Step 3) results in a reversal to the non-palmitoylated form, trafficking back to ER/Golgi membranes by a microtubule-independent pathway, and a new cycle of palmitoylation and targeting to a vesicular pathway. Bilayer membranes are shown as single lines for clarity. In reality, the lipid modifications interact only with the cytoplasmic leaflet of the bilayer. PAT, palmitoyl transferase; APT, acyl-protein thioesterase, ER, Endoplasmic reticulum; PM, plasma membrane; SVM synaptic vesicle membrane.

Table I.  Half-times of fluorescent protein recovery into the Golgi compartment following photobleaching.

Protein	Cell type	T½	Ref.
Palmitoylated proteins
N-Ras-YFP	MDCK	1.1 min	[14]
N-Ras-GFP	COS-7	0.8 min	[15]
H-Ras-YFP	MDCK	6.0 min	[14]
H-Ras-GFP	COS-7	0.6 min	[15]
GAD65-GFP	Neurons	3.0 min	[19]
GAD65-GFP	COS-7	2.6 min	[19]
(1–20)GAP43-YFP	MDCK	3.5 min	[14]
(1–32)Giα1-YFP	MDCK	1.7 min	[14]
(1–55)εNOS-YFP	MDCK	0.9 min	[14]
Multiple trimeric G-protein subunits	CHO	<1 min	[31]
Mono palmitoylated H-Ras
H-RasC181S-YFP	MDCK	38 sec	[14]
H-RasC184S-YFP	MDCK	41 sec	[14]
Palmitoylation deficient proteins
H-RasC181,184S-GFP	COS-7	<10 sec	[15]
N-RasC181S-GFP	COS-7	<10 sec	[15]
GAD65C30,45A-GFP	Neurons	1.7 sec	[19]
GAD65C30,45A-GFP	COS-7	5.3 sec	[19]
GAD65-GFP fast	Neurons	0.6 sec	[19]
GAD65-GFP fast	COS-7	2.4 sec	[19]

Table II.  Intracellular localization of mammalian DHHC family of palmitoyl transferases.

Protein	Localization	Reference
DHHC-1	ER	[65]
DHHC-2	ER/Golgi/PM	[59], [65]
DHHC-3	Golgi/PM	[59], [65], [70]
DHHC-4	Golgi	[65]
DHHC-5	PM	[65]
DHHC-6	ER	[65]
DHHC-7	Golgi/PM	[59], [65], [70]
DHHC-8	Golgi/PM	[59], [65], [67]
DHHC-9	ER/Golgi	[65]
DHHC-10	ER	[65]
DHHC-11	ER	[65]
DHHC-12	ER/Golgi	[65]
DHHC-13	ER	[65]
DHHC-14	ER	[65]
DHHC-15	Golgi	[65]
DHHC-16	ER	[65]
DHHC-17	Golgi/CV/SV	[45], [65], [66], [70]
DHHC-18	Golgi	[65]
DHHC-19	ER	[65]
DHHC-20	PM	[65]
DHHC-21	Golgi/PM	[59], [65]
DHHC-22	ER/Golgi	[65]

ER, Endoplasmic reticulum; PM, plasma membrane; CV, cytosolic vesicle; SV, synaptic vesicle.

Table III.  Mutations in DHHC proteins associated with pathology.

DHHC protein	Pathology	Substrate	Ref.
DHHC-2	Colorectal cancer (H)	CKAP4/p63 (D)	[63], [74]
		CD9, CD161 (H)	[64]
DHHC-8	Schizophrenia (H, M)		[67]
DHHC-9	X-linked mental retardation (H)		[75]
	Colorectal cancer (H)		[76]
DHHC-11	Bladder cancer (H)		[77]
DHHC-15	X-linked mental retardation (H)		[78]
Hip14/DHHC-17	Huntington disease (M)	Huntingtin (M)	[68]
	Synaptic transmission (D)	CSP, SNAP25 (D)	[66], [69]
Approximated	Abnormal patterning and
	planar cell polarity (D)	Partner of Dachs? (D)	[71]

H, human; M, mouse; D, Drosophila.

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