Insights Into the Mechanisms of Epilepsy from Structural Biology of LGI1–ADAM22

Cellular and Molecular Life Sciences (2020) 77:267–274 https://doi.org/10.1007/s00018-019-03269-0 Cellular andMolecular Life Sciences REVIEW Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22 Atsushi Yamagata1,2,3,4 · Shuya Fukai1,2,3 Received: 20 May 2019 / Revised: 5 August 2019 / Accepted: 9 August 2019 / Published online: 20 August 2019 © Springer Nature Switzerland AG 2019 Abstract Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identifed in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1–ADAM22. Keywords Epilepsy · LGI1 · ADAM22 · Synapse · Autoantibody · Chemical corrector Introduction receptor, was found to cause autosomal dominant sleep- related hypermotor epilepsy [3, 4], many mutations in ion About 1–2% of the population is sufered from epilepsy. To channel genes have been identifed as epilepsy-related muta- date, over 900 genes have been reported to be associated tions [5, 6]. Therefore, current antiepileptic drugs mainly with epilepsy, and many genetic mutations on these genes target ion channels. Non-ion-channel-type epilepsy-related are directly related to epilepsy [1, 2]. Since a mutation in proteins are another group of drug target for the development CHRNA4, encoding the α4 subunit of nicotinic acetylcholine of new therapeutic strategies for epilepsy. One of the best-characterized non-ion-channel-type epilepsy-related proteins is the leucine-rich repeat glioma- * Atsushi Yamagata inactivated protein 1 (LGI1), which is a neuronal secreted [email protected] protein [7–9]. To date, at least 43 mutations of LGI1 (29 * Shuya Fukai missense mutations and 14 deletion/truncation mutations) [email protected] have been found in autosomal dominant lateral temporal 1 Institute for Quantitative Biosciences, The University lobe epilepsy (ADLTE; also known as autosomal dominant of Tokyo, Tokyo 113-0032, Japan partial epilepsy with auditory features [ADPEAF]) families 2 Synchrotron Radiation Research Organization, The [7, 10–13]. In addition, autoantibodies against LGI1 in lim- University of Tokyo, Tokyo 113-0032, Japan bic encephalitis are associated with amnesia, seizures, and 3 Department of Computational Biology and Medical cognitive dysfunction [14–16]. LGI1 knockout mice show Sciences, Graduate School of Frontier Sciences, The severe epileptic phenotype [17–19], which is specifcally res- University of Tokyo, Chiba 277-8561, Japan cued by the neuronal expression of the LGI1 transgene [18]. 4 Present Address: Laboratory for Protein Functional Genetic, biochemical, and clinical studies have accumulated and Structural Biology, RIKEN Center for Biosystems the evidences of the strong connection between LGI1 and Dynamics Research, Yokohama, Kanagawa 230-0045, Japan Vol.:(0123456789)1 3 268 A. Yamagata, S. Fukai epilepsy, and LGI1 has been implicated in brain develop- Pathogenic mutations of LGI1 ment [20–22], neuronal excitability [19, 23, 24], and synaptic transmission [18, 25–27]. However, physiological func- As mentioned above, at least 28 missense mutations have tions of LGI1 still remain elusive. Recent structural studies been reported in patients with familial ADLTE (Table 1). on LGI1 and its receptor, ADAM22 [25], illustrate the trans- Among them, 19 mutations result in secretion-defective synaptic linkage mediated by the higher-order assembly of proteins presumably due to the failure of protein fold- LGI1–ADAM22 and shed light on the relationship between ing [12]. The C42R, C42G, C46R, C46F, C179R, and their mutations and pathogenesis [28]. C200R mutations are mapped onto the cysteine residues forming disulfde bonds in the N- and C-terminal caps of the LRR domain (Fig. 1a) [28], and these mutations LGI1 structure disturb the proper folding. The E383A mutation disrupts the Ca2+ coordination inside of the β-propeller structure LGI1 is a 60-kDa secreted protein, and predominantly (Fig. 1b, c). In addition, the C286R mutation disrupts the expressed in neuronal cells in the brain [7, 25]. LGI1 con- intra-molecular disulfde bond with Cys260 inside the sists of the N-terminal LRR domain and the C-terminal β-propeller structure (Fig. 1b). A recently found muta- epitempin-repeat (EPTP; also known as EAR) domain [28]. tion, P43R, is located in the N-terminal cap and causes a The structure of LGI1 LRR forms the central fve LRR secretion defect [13]. This mutant LGI1 in cortical neurons repeats, fanked by the N- and C-terminal caps (Fig. 1a). causes dysfunctional cortical neuronal migration, which The C-terminal EPTP domain comprises a seven-bladed might be related to the fact that LGI1-related epilepsies β-propeller, in which each blade is composed of a four- involve mainly the temporal lobe. On the other hand, the stranded antiparallel β-sheet (Fig. 1b). The N-terminal S473L and R474Q mutations are secretion competent strand is assembled with the C-terminal three strands to [12]. The S473L mutation substantially reduces the bind- close the propeller. The EPTP β-propeller structure resem- ing to ADAM22 [12]; whereas, the R474Q mutation disa- bles a WD40 domain. Structural alignment of each blade bles the assembly of the tripartite complex of ADAM22, reveals a WD-like motif, though the position of the WD-like ADAM23, and LGI1 [28]. Structural aspects of this com- motif in LGI1 EPTP is shifted by two residues from those plex are described below. in other canonical WD40 proteins. The unique features of LGI1 EPTP are the disulfde bond inside β-propeller and the coordinated Ca 2+, which stabilize the whole β-propeller structure (Fig. 1b, c). (a) (b) (c) V432E R407C S473L E383A E383 R474Q T380A R136W I122K C179R D381 A110D I122T C G493R I82T L154P E336 Ca2+ C46R F226C C46F L373S Ca2+ D334 N V382 P43R C286R N C L214P I298T E123K S145R C200R C260 C42R C42G N-cap LRR C-cap L232P F318C Fig. 1 Domain structures and pathogenic mutations of LGI1. a LGI1 mapped onto the LGI1 EPTP structure. Each blade of the β-propeller LRR structure. Pathogenic mutations are mapped onto the LGI1 LRR is diferently colored. The Ca2+ coordinated inside the β-propeller is structure. The N-cap, LRR, and C-cap regions are colored in light shown as a gray ball. A disulfde bond and N-glycans are shown as gray, light green, and light cyan, respectively. Disulfde bonds are sticks. c The close-up view of the Ca2+ coordination site. Glu383, shown as sticks. b LGI1 EPTP structure. Pathogenic mutations are whose mutation is pathogenic, coordinates Ca2+ via a water molecule 1 3 269 Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22 Table 1 Pathogenic missense Domain Mutation Secretion Efects Reference mutations on LGI1 N-cap C42R − Disruption of the disulfde bond with C48 [11, 12, 36] C42G − Disruption of the disulfde bond with C48 [11, 12, 37] P43R − Misfolding [13] C46R − Disruption of the disulfde bond with C55 [11, 12, 38, 39] C46F N.E. Disruption of the disulfde bond with C55 [40] LRR I82T N.E. Misfolding [41] A110D − Misfolding [11, 12, 36] I122K − Misfolding [11, 12, 42] I122T − Misfolding [12, 43] E123K − Misfolding [11, 12, 42, 44] R136W − Misfolding [11, 12, 42, 43] S145R − Misfolding [11, 12, 45] L154P − Misfolding [11, 12, 46] C-cap C179R − Disruption of the disulfde bond with C221 [12, 43] C200R − Disruption of the disulfde bond with C177 [11, 12, 47] L214P N.E. Misfolding [48] EPTP F226C N.E. Misfolding [49] L232P − Misfolding [11, 12, 50] C286R N.E. Disruption of the disulfde bond with C260 [51] I298T − Misfolding [11, 12, 36] F318C − Misfolding [11, 12, 52] L373S N.E. Misfolding [51] T380A − Misfolding [12, 53] E383A − Misfolding [7, 11, 12] R407C + unafected [12, 28, 54] V432E − Misfolding [11, 12, 47] S473L + Disruption of the binding to ADAM22 [11, 12, 37, 49] R474Q + Disruption of LGI1–LGI1 interaction [12, 24, 28, 55] G493R − Misfolding [12, 56] ADAM22 and other ADAM22 family proteins Mechanisms of the interaction between LGI1 and ADAM22 ADAM22 has been identifed as a receptor of LGI1 [25]. The LGI1–ADAM22 complex plays a critical role in The EPTP domain of LGI1 is sufficient for binding AMPA receptor-mediated synaptic transmission [18, 25, to ADAM22 [25]. The crystal structure of the LGI1 29]. ADAM22 belongs to a transmembrane ADAM met- EPTP–ADAM22 complex reveals that LGI1 EPTP binds alloprotease family [30]. However, the histidine residues to the metalloprotease domain of ADAM22 (Fig. 2a) [28]. coordinating the catalytic zinc ion are replaced with other Three aromatic residues in ADAM22 (Trp398, Tyr408, and residues in ADAM22 [31]. To our knowledge, it is likely Tyr409 in human ADAM22) stick into a hydrophobic pocket that ADAM22 solely functions as a receptor for LGI1 [25]. located at the rim of the EPTP propeller (Fig.

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