Molecular mechanisms of perilipin protein function in lipid droplet metabolism

Abstract

Perilipins are abundant lipid droplet (LD) proteins present in all metazoans and also in Amoebozoa and fungi. Humans express five perilipins, which share a similar domain organization: an amino‐terminal PAT domain and an 11‐mer repeat region, which can fold into amphipathic helices that interact with LDs, followed by a structured carboxy‐terminal domain. Variations of this organization that arose during vertebrate evolution allow for functional specialization between perilipins in relation to the metabolic needs of different tissues. We discuss how different features of perilipins influence their interaction with LDs and their cellular targeting. PLIN1 and PLIN5 play a direct role in lipolysis by regulating the recruitment of lipases to LDs and LD interaction with mitochondria. Other perilipins, particularly PLIN2, appear to protect LDs from lipolysis, but the molecular mechanism is not clear. PLIN4 stands out with its long repetitive region, whereas PLIN3 is most widely expressed and is used as a nascent LD marker. Finally, we discuss the genetic variability in perilipins in connection with metabolic disease, prominent for PLIN1 and PLIN4, underlying the importance of understanding the molecular function of perilipins.

Surface tension-driven sorting of human perilipins on lipid droplets

“…The importance of understanding the precise mechanisms of PLIN function on LDs is underscored by their diverse implications in different diseases. Mutations in PLIN1 and PLIN4 in particular have been linked to many metabolic phenotypes, and loss of function heterozygous mutations in PLIN1 and PLIN4 positively and negatively, respectively, correlate with metabolic disease (14, 60). Over-expression of PLIN2 and PLIN3 has been observed in a number of cancers and often correlates with higher proliferation and poor prognosis (61).…”

“…Interestingly, the two PLINs specific for mature adipocytes (42)(43)(44)56) are the most different: PLIN1 is not soluble whereas PLIN4 is a gigantic intrinsically disordered soluble protein (14). In resting differentiated adipocytes, these contrasting properties translate into different localization.…”

“…Due to their high abundance and ability to stabilize LDs, PLINs are often referred to as LD coats (10–12). In humans, the PLIN family contains 5 members (PLIN1-5), which show notable differences in their tissue and subcellular distribution, mode of regulation, and protein interactions (12–14). PLINs contain three main regions: (i) an N-terminal PAT domain, the structure of which is not known but which might contain three helices (15), (ii) a central disordered region, which has been shown to target lipid droplets by providing 3-11 amphipathic helices (AH) that bind to the LD interface (16–20), and (iii) a C-terminal domain, whose structure has been solved in the case of PLIN3 as forming a 4-helix bundle (21).…”

“…This uneven distribution might result from differences in protein turnover during cell differentiation and/or from intrinsic differences in the physicochemical properties of PLINs. These include the amino-acid composition of their AH regions, the presence of additional hydrophobic regions, or the ability of the PAT region or the 4-helix bundle to undergo conformational changes (14, 15, 20, 27).…”

“…Due to their high abundance and ability to stabilize LDs, PLINs are often referred to as LD coats (10)(11)(12). In humans, the PLIN family contains 5 members (PLIN1-5), which show notable differences in their tissue and subcellular distribution, mode of regulation, and protein interactions (12)(13)(14).…”