Year: 2017
Type: review
Abstract: Chloroplasts descended from a free-living cyanobacterium acquired through endosymbiosis roughly one billion years ago. Three major groups comprising the Archaeplastida, photosynthetic eukaryotes bearing primary plastids, arose subsequently: the glaucophytes, red algae (red lineage), and Viridiplantae, also called Chloroplastida, encompassing green algae and land plants (green lineage; Keeling, 2010; Zimorski et al., 2014). Beyond carrying out photosynthesis, plastids perform many other vital functions, such as fatty acid and amino acid synthesis, and are therefore essential organelles (Pyke, 2009). Plastid division increases chloroplast populations during leaf development, crucial for photosynthetic capacity (Leech and Baker, 1983), and ensures that plastids are faithfully inherited during cytokinesis. Similar to their free-living ancestors, plastids are propagated through division of preexisting organelles. This process is powered by a macromolecular machine with ring-shaped contractile complexes on both the inner and outer envelope membranes (for review, see Miyagishima et al., 2011; Falconet, 2012; Yoshida et al., 2012; Osteryoung and Pyke, 2014). The division machinery is a mosaic of components of both endosymbiotic and host origin that must cooperate to divide the organelle (Fig. 1B). The stromal components are largely endosymbiont derived, whereas the cytosolic components are strictly eukaryotic. In land plants and many algae, all the plastid division proteins are encoded in the nucleus, but some algae retain a few that are plastid encoded (Onuma et al., 2017). Here, we highlight developments in the division of chloroplasts, particularly in land plants, with an emphasis on findings published since the previous Plant Physiology Update on this topic (Miyagishima, 2011). We refer readers to other reviews for information on the division of other plastid types, including secondary plastids, and for a more evolutionary perspective (for review, see Miyagishima, 2011; Miyagishima et al., 2011, 2014; Pyke, 2016). Working model of the positioning, assembly, and dynamics of the chloroplast division machinery in angiosperms based primarily on studies in Arabidopsis but informed by studies in C. merolae and other organisms. A, Diagram showing chloroplasts within a leaf mesophyll cell. B, Cyanobacterial (endosymbiotic) or host (eukaryotic) origin of chloroplast division components in angiosperms. C, FtsZ1 and FtsZ2 self-assemble as dynamic heteropolymers, possibly with mixed stoichiometry (Olson et al., 2010; Chen et al., 2017); protofilaments may possibly associate laterally to form the Z ring at the division site (Lutkenhaus and Du, 2017). Positioning of the Z ring is confined to the midzone by the chloroplast Min system, comprising ARC3, MCD1, MinD, and MinE, which inhibits Z-ring assembly at nondivision sites. ARC3 acts downstream of MinD and MinE as the direct inhibitor of Z-ring assembly (Zhang et al., 2013). MCD1, a transmembrane IEM protein, recruits MinD to the membrane (Nakanishi et al., 2009), where MinE is also colocalized (Miyagishima et al., 2011). ARC3 interacts with both MinD and MinE (Maple et al., 2007). Thus, we hypothesize that ARC3 forms a complex with MinD and MinE that is tethered to the membrane by MCD1. The exact localization pattern of ARC3 and the inhibitory mechanisms of ARC3 on Z-ring assembly are unclear (indicated by the question marks). The chloroplast Min-system components also localize partly to the division site (Shimada et al., 2004; Nakanishi et al., 2009; Miyagishima et al., 2011), where they may promote Z-ring remodeling during division (Johnson et al., 2015). D, Overview of the four contractile ring structures formed across the two envelope membranes. The composition of the inner PD ring is unknown and is not shown in further panels. The outer PD ring is synthesized by PDR1 (not shown) in the red alga C. merolae (Yoshida et al., 2010). The order of assembly based on studies in C. merolae is Z ring, inner PD ring, outer PD ring, DRP5B ring (Miyagishima et al., 2001, 2003). E to I, Stepwise assembly and dynamics of the division complex at the middle of the chloroplast. E, Tethering of the Z ring to the IEM is achieved mainly through interaction of the conserved FtsZ2 C-terminal peptide (CTP) with ARC6 (Maple et al., 2005), which probably stabilizes the Z ring and facilitates its assembly (Vitha et al., 2003; Johnson et al., 2013). F, ARC6 recruits PDV2 to the division site through direct interaction between their C-terminal IMS regions (Glynn et al., 2008). Dimerization of the cytosolic regions of two PDV2 molecules induces dimerization of two ARC6 molecules (Wang et al., 2017). G, PARC6 acts downstream of ARC6 to localize PDV1 to the division site through direct interaction between their C-terminal IMS regions (Glynn et al., 2009; Zhang et al., 2016). Based on ARC6-PDV2 studies (Wang et al., 2017), PDV1 dimerization might also promote PARC6 dimerization (indicated by question mark). H, In C. merolae, PDR1 (not shown) is recruited from the cytosol to construct the outer PD ring, composed of polyglucan fibrils (Yoshida et al., 2010). In Arabidopsis, PDV1 and PDV2 function together to recruit DRP5B from the cytosol (Miyagishima et al., 2006) to form the DRP5B ring (Gao et al., 2003; Miyagishima et al., 2003; Holtsmark et al., 2013). Coordination of the stromal Z ring and the cytosolic DRP5B ring is established through the ARC6-PDV2 and PARC6-PDV1 complexes. Whether the outer PD ring interacts with the PDV proteins is unclear. I, Remodeling of the Z ring and constriction. We speculate that PARC6 recruits ARC3 to the division site via interaction with the ARC3 MORN domain, enabling ARC3 to interact with FtsZ in the Z ring. The latter interaction may be facilitated by interaction of PARC6 with the FtsZ2 CTP (Zhang et al., 2016). As an FtsZ assembly inhibitor, ARC3 activation at the division site may promote Z-ring remodeling. MinD, MinE, and MCD1 also localize partly to the division site (Nakanishi et al., 2009; Miyagishima et al., 2011; not shown in I). Dynamic remodeling of the Z ring probably also depends on FtsZ1 (TerBush and Osteryoung, 2012; Yoshida et al., 2016; Terbush et al., 2018). OEM, Outer envelope membrane; IMS, intermembrane space; IEM, inner envelope membrane; MORN, membrane occupation and recognition nexus domain of ARC3; PD ring, plastid-dividing ring. A central and nearly ubiquitous component of the chloroplast division machinery is FtsZ, a tubulin-like cytoskeletal GTPase that descended from the cyanobacterial ancestor of chloroplasts, where it functioned in cell division (Erickson et al., 2010; Miyagishima et al., 2011; TerBush et al., 2013; Osteryoung and Pyke, 2014; Haeusser and Margolin, 2016). In both bacteria and chloroplasts, FtsZ assembles into a contractile “Z ring” inside the cell or organelle that defines the division site (Fig. 2; Box 1; Friedman and Nunnari, 2014; Addinall et al., 1996; Beech et al., 2000; Gilson et al., 2003; Bilsson-Filho et al., 2017; Osawa et al., 2009; Rothfield et al., 2005; Yang et al., 2017; Wagstaff et al., 2017; Strepp et al., 1997; Nishida et al., 2003; Lutkenhaus et al., 1980; Wang et al., 2017). Purified FtsZ undergoes GTP-dependent self-assembly into single-stranded polymers called protofilaments. Because the GTPase active site is formed within the subunit interface by the interaction of two monomers, polymerization catalyzes GTP hydrolysis. Hydrolysis destabilizes the interface, leading to protofilament fragmentation and subunit dissociation (Mukherjee and Lutkenhaus, 1998; Scheffers et al., 2002; Redick et al., 2005; Huecas et al., 2007; Chen and Erickson, 2009; Erickson et al., 2010). Released subunits can exchange nucleotides and recycle back into protofilaments. This dynamic GTPase-dependent turnover was essential for constriction of Z rings reconstituted on tubular liposomes (Osawa et al., 2008; Osawa and Erickson, 2011) and is likely required for Z-ring constriction in vivo. Immunofluorescence localization of the contractile Z ring in chloroplasts and cyanobacterial cells during division. A, Arabidopsis FtsZ2-1 (AtFtsZ2-1) detected with an anti-AtFtsZ2-1 antibody (McAndrew et al., 2001) in mesophyll cells of a fully expanded leaf obtained from a 3-week-old plant (Col-0). B, FtsZ in the cyanobacterium Synechococcus elongatus PCC 7942 (SeFtsZ) detected with an anti-Anabaena FtsZ antibody (Agrisera). Green, FtsZ; magenta, chlorophyll fluorescence. Bars, 5 μm. Because most bacteria have only a single FtsZ gene, bacterial Z rings are composed of homopolymers. In contrast, the majority of photosynthetic eukaryotes appear to encode two plastid-targeted, stroma-localized paralogs of FtsZ (Osteryoung and Vierling 1995; McAndrew et al., 2001; Leger et al., 2015; Box 1). These are called FtsZ1 and FtsZ2 in the green lineage, where they appear to be universally conserved, and FtsZA and FtsZB in red algae (Miyagishima et al., 2004; TerBush et al., 2013). FtsZ1 and FtsZ2 colocalize to Z rings in vivo (McAndrew et al., 2001; Vitha et al., 2001), are both required for normal chloroplast division in Arabidopsis (Arabidopsis thaliana; Osteryoung et al., 1998; Yoder et al., 2007; Schmitz et al., 2009), and coassemble in heteropolymers (Olson et al., 2010; TerBush and Osteryoung, 2012; Yoshida et al., 2016; Fig. 1). FtsZ2 and FtsZA are structurally more similar to bacterial FtsZs, in that they both retain a conserved C-terminal peptide (CTP), which in bacteria interacts with membrane proteins to anchor Z rings to the plasma membrane (Ma and Margolin, 1999; Vaughan et al., 2004; Margolin, 2005; Haeusser and Margolin, 2016). Similarly, the Arabidopsis FtsZ2 CTP interacts with two proteins in the chloroplast inner envelope membrane (IEM; Fig. 1, E–G; described below). In contrast, FtsZ1 and FtsZB lack the CTP, and no interaction between FtsZ1 and any membrane protein has been detected, suggesting its presence in the Z ring is a consequence of coassembly with FtsZ2 (Maple et al., 2005; Glynn et al., 2008; Zhang et al., 2016). Recently, FtsZA and FtsZB from the red alga Galdieria sulphuraria were also shown to copolymerize in vitro (Chen et al., 2017), indicating that FtsZ heteropolymerization is a conserved feature and may be the physiologically relevant state. Studies of FtsZ dynamics in heterologous yeast systems are beginning to provide insight into the functional significance of heteropolymerization. These systems lack FtsZ and any assembly the assembly and dynamic of FtsZ proteins to be et al., 2008; TerBush et al., 2016; Yoshida et al., 2016). of Arabidopsis FtsZ2 and were in the yeast structures in the cytosol (TerBush and Osteryoung, as FtsZ2 and FtsZ1 in vitro et al., 2005; et al., et al., 2010; et al., 2010). that a of subunit turnover and colocalized in which were more dynamic Similar were obtained for sulphuraria FtsZA and in were dynamic and were more dynamic et al., 2017). In a Yoshida et reconstituted Z rings in the yeast by a Osawa et al., to the of enabling it to to the plasma membrane in the yeast into a ring, but and the in the ring, and rings were more dynamic both of rings be to and rings more These with studies of Arabidopsis et al., 2007; McAndrew et al., 2008; Schmitz et al., 2009), that the more FtsZ2 and FtsZA proteins the and to chloroplast Z FtsZ1 and FtsZB Z-ring dynamics through The by which FtsZ1 and FtsZB protofilament turnover is not but one is that they into This is partly by showing that protofilaments were more dynamic protofilaments in vitro (Chen et al., 2017). of a conserved required for GTP turnover of and in as based on the GTPase-dependent turnover of bacterial FtsZ described the in and but not turnover of suggesting their dynamic is not on GTPase (TerBush and Osteryoung, 2012; Terbush et al., 2017). studies provide that the functional and coassembly of plastid a for Z-ring dynamics in and two FtsZ are also in bearing secondary plastids or that retain FtsZ (Miyagishima et al., 2004; Leger et al., 2015; Box 1). a FtsZ is in a of photosynthetic where its may be with the of a chloroplast 2; and 2014; and 2017; et al., 2016; et al., 1997; et al., 2003; et al., 2009; and 2010; et al., et al., et al., 2017). The Z ring is the to at the division site (Miyagishima et al., 2001; Fig. and its likely the of downstream In Z-ring is by a called the Min that self-assembly of Z rings but at the division site Miyagishima et al., 2005; et al., 2014; et al., in Lutkenhaus, 2007; and Margolin, 2013). In and et al., 2017), the Min the direct inhibitor of FtsZ the cell through a by MinD and MinE, which function as of localization of cyanobacterial MinD and MinE acquired through endosymbiosis have been in the green and localize to the where they in the of chloroplast division and Z-ring to in bacteria et al., 2000; et al., 2001; Vitha et al., 2003; et al., 2004; and 2005; Glynn et al., 2007; et al., 2008). in many has been and by the stromal protein ARC3 and of et al., 2004; et al., 2007). A for ARC3 was by the of Arabidopsis and which chloroplast Z and of chloroplast division leading to in chloroplast and (Glynn et al., 2007; et al., 2007; Fig. of bacterial et al., and Margolin, 1999; Box ARC3 interacts with and and inhibits their assembly in (Maple et al., 2007; TerBush and Osteryoung, 2012; Zhang et al., 2013). in Arabidopsis chloroplast and FtsZ (Maple et al., 2007; Zhang et al., in and et al., et al., 2017; Box the in Arabidopsis MinD and et al., 2000; Glynn et al., 2007; Fig. were in the of ARC3, with a for proteins as ARC3 (Zhang et al., 2013). These findings established ARC3 as a functional for and the inhibitor of Z-ring assembly in Arabidopsis ARC3 is not in all including with to et al., 2008; Osteryoung and Pyke, have not been and Z-ring localization in Arabidopsis plants and chloroplast division most of chloroplasts (Osteryoung and Pyke, 2014). A, by and Z-ring localization detected by in mesophyll The (Zhang et al., is in the all are in of FtsZ localization were from Miyagishima et and and Zhang et and with and by the of Plant Green, FtsZ; chlorophyll fluorescence. B, in cells from leaf cells chloroplasts mesophyll and the are more chloroplasts in and division in and Bars, μm. ARC3 and and may FtsZ assembly by acts by protofilament at subunit with Z-ring proteins for FtsZ and protofilament and Lutkenhaus, 2010; Lutkenhaus and Du, 2017). ARC3 an it conserved required for GTP and (Shimada et al., This may interact with FtsZ (Maple et al., FtsZ subunits and ARC3 may also have assembly inhibitory it is unknown MinD, MinE, and ARC3 in chloroplasts and the localization of ARC3 is not the of ARC3 in Z-ring at nondivision that ARC3 and MinD must localize at partly to membrane regions from the localization is by showing that MinD and MinE localize partly to structures the envelope membrane (Nakanishi et al., 2009; Miyagishima et al., 2011; Fig. the chloroplast Min in Arabidopsis from bacterial systems in other In MinD to the membrane where it recruits 2007). In Arabidopsis, MinD with the membrane the transmembrane protein MCD1 (Nakanishi et al., 2009; Fig. ARC3 might be recruited to the membrane by an but this is not only interacts with MinD, whereas ARC3 interacts with both MinD and MinE (Maple et al., which colocalize in vivo (Miyagishima et al., 2011). the complex ARC3, MinD, MinE, MCD1, and FtsZ be for the chloroplast Min Z-ring ARC3 also with FtsZ to the (Shimada et al., likely through interaction with the IEM transmembrane protein ARC6 also called Fig. 1, and I). Chloroplasts in Arabidopsis and Z rings in and Fig. and FtsZ PARC6 chloroplasts with FtsZ similar to ARC3 These PARC6 as an of FtsZ assembly and Z-ring (Glynn et al., 2009; Zhang et al., 2009). The stromal of PARC6 interacts with both FtsZ2 and ARC3 (Zhang et al., 2016; Fig. and in vivo ARC3 may Z-ring remodeling (Johnson et al., 2015). interaction is by a C-terminal of ARC3 called the and domain (Glynn et al., 2009; Zhang et al., 2016; Fig. the MORN domain also inhibits ARC3 interaction with FtsZ (Maple et al., 2007; Zhang et al., 2013). These and findings a model in which PARC6 may ARC3 and FtsZ into at the division where interaction the MORN domain, enabling ARC3 to interact with FtsZ (Zhang et al., 2016). The of ARC3 on FtsZ assembly Z-ring remodeling during constriction. This be at where Z-ring is fully (Fig. MinD, MinE, and MCD1 may also to Z-ring remodeling they also localize partly to the (Nakanishi et al., 2009; Miyagishima et al., 2011; Fig. PARC6 has also been detected plastid which may its at formed division (Glynn et al., 2009). ARC3 is also or at this Z-ring assembly and to of a division site (Osteryoung and Pyke, 2014; Zhang et al., 2016). These are but for The outer chloroplast division machinery two contractile the ring, and the outer plastid-dividing ring (Fig. 1, and I). also called et al., is a of the (Gao et al., 2003; Miyagishima et al., which constriction of many organelle and 2015). Arabidopsis have chloroplasts that an suggesting DRP5B is required for constriction and DRP5B is recruited from cytosolic to the of the chloroplast by the proteins PDV1 and PDV2 (Gao et al., 2003; Miyagishima et al., Fig. which may its GTPase et al., 2013). DRP5B also in the division of and indicating in the of organelles (Zhang and 2010; and 2012; et al., 2018). The outer PD ring (Fig. 1, D, H, and is an contractile in algae and land plants and most in the red alga merolae et al., 2008; Miyagishima et al., 2011; Yoshida et al., where it is composed primarily of polyglucan These are probably synthesized by a that from the cytosol to a ring at the site and division (Yoshida et al., 2010). DRP5B is recruited to the chloroplast of the outer PD ring and was to provide the for of during constriction (Yoshida et al., Yoshida et al., 2010). the of PDR1 outer composition have been in other organisms. division the and constriction of the stromal and cytosolic contractile across the two envelope membranes. The stromal machinery to an contractile the inner PD ring (Fig. of unknown composition et al., 2008; no on of the PD rings is but in Arabidopsis, between the Z ring and DRP5B ring is by two of ARC6 and PARC6 in the IEM, and PDV1 and PDV2 in the (Fig. 1, ARC6 descended from the cyanobacterial cell division protein called and is conserved the green and 2002; Vitha et al., 2003; et al., 2004; et al., 2009). et al., one or two chloroplasts with FtsZ ARC6 bearing chloroplasts, FtsZ These that ARC6 FtsZ assembly and probably stabilizes the Z ring et al., Vitha et al., 2003). ARC6 the IEM with its to the and its into the intermembrane Fig. The stromal of ARC6 to FtsZ2 via the CTP and probably acts as the primary membrane for the Z ring (Johnson et al., 2013; Fig. The IMS interacts with the C-terminal IMS of the protein PDV2 (Fig. and this interaction is required for PDV2 localization to the division site (Glynn et al., 2008). A similar between PARC6 and PDV1 (Fig. which arose by and of ARC6 and and may both be confined to plants (Miyagishima et al., Glynn et al., 2009). In PDV2 and PDV1 recruit Thus, ARC6 and PARC6 information from the stromal Z ring to the of the chloroplast through PDV2 and PDV1 to localize the DRP5B ring. The and presence of laterally Z rings the division site in the chloroplasts of Arabidopsis and (Fig. that division is but not in (Miyagishima et al., 2006) and that information is also from the to division complexes during normal chloroplast division. A interaction and in Arabidopsis for this (Wang et al., 2017). The that of the IMS of PDV2 into a formed by a conserved of the et al., and that a PDV2 induces in the of a (Fig. dimerization on interaction between the cytosolic regions of the two PDV2 A of PDV2 ARC6 rings in vivo of the single ring in (Wang et al., 2017). Thus, PDV2 dimerization on the cytosolic information inside the in the of a single ARC6 ring. not in this ARC6 dimerization may also with the chloroplast Min system, to the or of a Z ring in the by an unknown (Wang et al., 2017). are many of inner and outer complexes. the of DRP5B in the division DRP5B to the chloroplast probably direct interaction with PDV proteins (Miyagishima et al., Holtsmark et al., 2013). DRP5B might the dimerization of leading to ARC6 and Z This is by the of a DRP5B et al., 1996; et al., that also Z rings the middle of its chloroplasts (Miyagishima et al., Fig. question is interaction (Fig. might also information from to inside the chloroplast. the might be to Z since PARC6 Z-ring probably at partly through its interaction with ARC3 (Glynn et al., 2009; Zhang et al., 2016; Fig. A few other proteins with also to chloroplast division and 2013; Osteryoung and Pyke, 2014). of chloroplasts to two a protein partly the plasma membrane and partly on the chloroplast et al., 2011), and in the et al., 2004; Chen et al., 2009; et al., proteins were to chloroplast to the is a stromal protein with the IEM that some to the bacterial inhibitor and may an in (Maple et al., 2004; et al., on chloroplast division is is particularly in land plants with chloroplasts cell division is not with cell division (Miyagishima, 2011; et al., 2016). Here, we highlight on of division a endosymbiotic and organelle the host to between endosymbiont division and host cell et al., 2016). to the and from the chloroplast endosymbiosis of this by most host 2010). Miyagishima et of the major of primary algae to the of chloroplast division and proteins during the cell that all the were during Z-ring and chloroplast division were FtsZ from the which was (Miyagishima et al., Z-ring in C. was confined to the In contrast, and other chloroplast division in the plastid of the green algae and were but chloroplast division during The that of that in the is host of in the plastid and that the of chloroplast division (Miyagishima et al., The mechanisms the of and chloroplast division unclear. that from the chloroplast also the host cell et al., 2007; et al., 2011; et al., 2016). A in C. merolae et al., that was in chloroplast which is to FtsZ (Vitha et al., 2001), was by FtsZ to assembly of the division of the and of B, were in the the chloroplast division complex to of chloroplast division no These that assembly of the chloroplast division machinery a on the cell the is between Z-ring and DRP5B et al., 2016). this is to the is has been in the of chloroplast division in et al., et al., and this is partly through of PDV of the PDV proteins in chloroplast and chloroplast in Arabidopsis and indicating that PDV1 and PDV2 the of chloroplast division et al., 2009; et al., 2017). of or a similar in Arabidopsis, and plants of PDV1 and PDV2 but not other division Similarly, of with PDV2 and chloroplast division et al., 2009). Recently, et that of chloroplast and cell division. Because has similar they that and cooperate in the of chloroplast division. PDV2 was not in suggesting chloroplast division by a et al., 2015). that chloroplast division is in in et al., and PDV were in the chloroplast division and Based on the that might chloroplast division through the of protein which chloroplast division et al., A in Arabidopsis the a of and its as of and chloroplast division (Gao et al., 2013). and chloroplasts, similar to (Fig. of a downstream of or of in only the or chloroplast division suggesting that and through et al., 2015). Recently, et that the chloroplast division in of to in chloroplast membranes chloroplast a of chloroplasts, similar to of PDV proteins et al., 2009). this was primarily to of DRP5B from the cytosol to the chloroplast and not to PDV protein PDV1 and PDV2 both to but the of on chloroplast division was largely in but not Based on and other the that PDV1 interaction with in the chloroplast envelope PDV1 for which may the of chloroplast division. These findings in the of chloroplast division et al., 2015). many of the in chloroplast division have been particularly in Arabidopsis, we lack of many of their and functional as components of a dynamic and functional studies evolutionary in the composition of the division machinery (Miyagishima et al., 2011). ARC6 descended from a cyanobacterial cell division and 2002; Vitha et al., no ARC6 or other protein for the Z ring has been in red We it may from division of the envelope membranes We have information the division of plastid other chloroplasts or other of plastid such as a and Pyke, Pyke, 2016). The mechanisms the of chloroplast (Pyke, 1999; et al., 2016). The to which division is with and 2010; and 2011; and and other is plastid division is and with cell division and chloroplast and plant and and 2013; et al., 2016; see it is in the of plastid to be We Min Zhang for and and of the Osteryoung for and
Source: PLANT PHYSIOLOGY
DOI: 10.1104/pp.17.01272
Institution: Michigan State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,851
Awards: G1903077474, G222768804, Assembly, Dynamics and Regulation of Chloroplast FtsZ, Cyanobacterial Cell Division: Mechanisms and Inputs Towards the Decision to Divide, MECHANISMS OF CHLOROPLAST DIVISION IN PLANTS, FUNCTIONAL ANALYSIS OF ARC6 AND FTN2, ORTHOLOGOUS REGULATORS OF CHLOROPLAST AND CYANOBACTERIAL CELL DIVISION, Mechanistic Insights Into Chloroplast FtsZ Assembly and Dynamics
OpenAlex ID: W2766357374