Structural snapshots reveal how the plant KCS6-CER2 complex drives very-long-chain fatty acid elongation

Researchers from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (GIBH, CAS), together with collaborators, have uncovered the molecular mechanism by which the plant-specific KCS6-CER2 enzyme complex catalyzes very-long-chain fatty acid (VLCFA) elongation. Published in Molecular Plantunder the title “Structural snapshots of plant-specific KCS6-CER2 complex reveal the elongation mechanism of very-long-chain fatty acids,” the study provides the first complete structural reconstruction of the condensation reaction underlying plant VLCFA elongation.

Very-long-chain fatty acids (VLCFAs; ≥C20) are essential components of membrane lipids, sphingolipids, suberin, and cuticular waxes. They play critical roles in reducing water loss, protecting plants against pathogen invasion, and enabling adaptation to terrestrial environments. VLCFAs also serve as valuable renewable feedstocks for pharmaceuticals, cosmetics, lubricants, and other bio-based products.

In plants, VLCFAs are synthesized by the endoplasmic reticulum-localized fatty acid elongase (FAE) complex through iterative two-carbon elongation cycles. The initial condensation reaction, catalyzed by β-ketoacyl-CoA synthase (KCS), is both the rate-limiting and chain-length-determining step of the pathway (Figure 1A). Unlike animals and fungi, which rely on elongases, plants have evolved a distinct elongation system in which KCS cooperates with ECERIFERUM2 (CER2) proteins. However, the molecular basis of this process remains unresolved. In particular, the lack of structural information on key catalytic intermediates has obscured how the complex recognizes substrates, extends acyl chains, and forms products.

Selaginella moellendorffii, an early-diverging extant vascular land plant, represents one of the earliest known lineages to possess the cooperative KCS6-CER2 elongation module. It therefore provides both an important system for elucidating the mechanism of the plant-specific VLCFA elongation machinery and a valuable evolutionary model for tracing the emergence and evolution of this system during the early colonization of land by plants.

Using S. moellendorffii as a model, the researchers determined a series of cryo-electron microscopy (cryo-EM) structures spanning the complete condensation reaction catalyzed by the KCS6-CER2 complex. These structures captured the apo state, a C22:0 acyl-enzyme intermediate, the malonyl-CoA-bound state, and the C24:0 β-ketoacyl-CoA product-bound state. Together, they reveal the complete sequence of molecular events underlying substrate recognition, acyl-chain loading, two-carbon condensation, and product formation (Figure 1B).

The study also identified a previously unrecognized lateral acyl-CoA-binding cavity adjacent to the catalytic tunnel. The researchers captured a C22:0 acyl-CoA molecule within this cavity, and complementary functional analyses showed that the cavity is essential for efficient VLCFA biosynthesis. This finding expands the current model of substrate handling by revealing an additional acyl-CoA-binding site that may facilitate substrate processing during successive elongation cycles.

Comparative structural and phylogenetic analyses further showed that both the cooperative catalytic mechanism and the key structural features of the KCS6-CER2 complex are highly conserved across vascular plants. These results suggest that the KCS6-CER2-mediated VLCFA elongation module emerged early during land plant evolution and has been retained throughout vascular plant diversification.

By revealing the complete structural basis of plant-specific VLCFA elongation and identifying a previously unknown acyl-CoA-binding cavity, this work advances our understanding of plant lipid metabolism. It also provides new insights into the molecular innovations that supported plant adaptation to terrestrial environments and establishes a structural foundation for engineering plant wax biosynthesis, improving drought and stress tolerance, and developing high-value plant-derived lipid products.

Figure 1. Schematic illustration of the molecular mechanism by which the KCS6-CER2 enzyme complex catalyzes very-long-chain fatty acid elongation in plants.

The study was jointly led by Prof. WANG Qianmin of GIBH, Prof. CHENG Yunjiang of Huazhong Agricultural University, and Prof. XU Youwei of Guangzhou Medical University, who served as co-corresponding authors. Dr. WANG Yang of GIBH and Dr. WANG Haiyan of Huazhong Agricultural University contributed equally as co-first authors. Academician DENG Xiuxin of Huazhong Agricultural University provided important guidance. Cryo-EM data collection was supported by the Gao Feng Cryo-EM Center at the Shanghai Institute of Materia Medica.

This work was supported by the Key International (Regional) Joint Research Program of NSFC (32320103005); the Foundation of Hubei Hongshan Laboratory (2021hszd009); the China Agriculture Research System of MOF and MARA (CARS-26).

Contacts:

WANG Qianmin, Ph.D., Principal Investigator

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530.

Email: wang_qianmin@gibh.ac.cn