1.C.81 The Arenicin (Arenicin) Family The solution structure and the mode of action of arenicin isoform 1, an antimicrobial peptide with a unique 18-residue loop structure, from the lugworm Arenicola marina have been elucidated (Andra et al., 2007). Arenicin folds into a two-stranded anti-parallel β-sheet. It exhibits high antibacterial activity against Gram-negative and positive bacteria, as well as yeast. Bacterial killing occurs within minutes and is accompanied by membrane permeabilisation, membrane detachment, and release of cytoplasmic constituents (Andra et al., 2007). Arenicin is a hydrophilic protein, 202 aas long with a single N-terminal hydrophobic region. The last 21 residues (182-202 aas) form the processed active peptide. The protein also contains a BRICHOS domain (pfam 64089) found in proteins involved in dementia and cancer. The full length protein is homologous to the chondromodulin-1 precursor (P17404) also called 'leukocyte cell-derived chemotaxin-1' of H. sapiens.
References:
Andrä, J., I. Jakovkin, J. Grötzinger, O. Hecht, A.D. Krasnosdembskaya, T. Goldmann, T. Gutsmann, and M. Leippe. (2008). Structure and mode of action of the antimicrobial peptide arenicin. Biochem. J. 410(1): 113-122.
Cegarra, C., C. Chaves, C. Déon, T.M. Do, B. Dumas, A. Frenzel, P. Kuhn, V. Roudieres, J.C. Guillemot, and D. Lesuisse. (2022). Exploring ITM2A as a new potential target for brain delivery. Fluids Barriers CNS 19: 25.
Gong, Y., J. Wu, H. Qiang, B. Liu, Z. Chi, T. Chen, B. Yin, X. Peng, and J. Yuan. (2008). BRI3 associates with SCG10 and attenuates NGF-induced neurite outgrowth in PC12 cells. BMB Rep 41: 287-293.
Mandal, A.K. and D.B. Mount. (2019). Interaction Between ITM2B and GLUT9 Links Urate Transport to Neurodegenerative Disorders. Front Physiol 10: 1323.
Martin, T.E., C.T. Powell, Z. Wang, S. Bhattacharyya, M.M. Walsh-Reitz, K. Agarwal, and F.G. Toback. (2003). A novel mitogenic protein that is highly expressed in cells of the gastric antrum mucosa. Am. J. Physiol. Gastrointest Liver Physiol 285: G332-343.
Martins, F., I. Santos, O.A.B. da Cruz E Silva, S. Tambaro, and S. Rebelo. (2021). The role of the integral type II transmembrane protein BRI2 in health and disease. Cell Mol Life Sci. [Epub: Ahead of Print]
Matsuda, S. and T. Senda. (2019). BRI2 as an anti-Alzheimer gene. Med Mol Morphol 52: 1-7.
Matsuda, S., Y. Matsuda, and L. D''Adamio. (2009). BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2. J. Biol. Chem. 284: 15815-15825.
Mukherjee, S., N. Sengupta, A. Chaudhuri, I. Akbar, N. Singh, S. Chakraborty, A.R. Suryawanshi, A. Bhattacharyya, and A. Basu. (2018). PLVAP and GKN3 Are Two Critical Host Cell Receptors Which Facilitate Japanese Encephalitis Virus Entry Into Neuron.s. Sci Rep 8: 11784.
Shenkarev, Z.O., S.V. Balandin, K.I. Trunov, A.S. Paramonov, S.V. Sukhanov, L.I. Barsukov, A.S. Arseniev, and T.V. Ovchinnikova. (2011). Molecular mechanism of action of β-hairpin antimicrobial peptide arenicin: oligomeric structure in dodecylphosphocholine micelles and pore formation in planar lipid bilayers. Biochemistry 50: 6255-6265.
Van den Plas, D. and J. Merregaert. (2004). Constitutive overexpression of the integral membrane protein Itm2A enhances myogenic differentiation of C2C12 cells. Cell Biol Int 28: 199-207.
Wohlschlegel, J., M. Argentini, C. Michiels, C. Letellier, V. Forster, C. Condroyer, Z. He, G. Thuret, C. Zeitz, T. Léger, and I. Audo. (2021). First identification of ITM2B interactome in the human retina. Sci Rep 11: 17210.
Yao, W., T. Yin, M.D. Tambini, and L. D''Adamio. (2019). The Familial dementia gene ITM2b/BRI2 facilitates glutamate transmission via both presynaptic and postsynaptic mechanisms. Sci Rep 9: 4862.
Examples:
TC#	Name	Organismal Type	Example
1.C.81.1.1	Arenicin-1 precursor (202 aas). The processed pore-forming β-hairpin antimicrobial peptide corresponds to residues 182-202 (Andrä et al., 2008; Shenkarev et al., 2011). Low-conductivity pores were detected in the phosphatidylethanolamine-containing lipids and high-conductivity pores in anionic lipids. The measured conductivity levels agreed with the model in which arenicin antimicrobial activity was mediated by the formation of toroidal pores assembled of two, three, or four β-structural peptide dimers and lipid molecules (Shenkarev et al., 2011).	Animals	*Arenicin-1 of Arenicola marina* (lugworm) (Q5SC60)**

1.C.81.1.10	Gastrokine-1, GKN1 of 199 aas and 2 TMSs, one N-terminal and one C-terminal. It has mitogenic activity and may be involved in maintaining the integrity of the gastric mucosal epithelium (Martin et al. 2003).		GKN1 of Homo sapiens

1.C.81.1.2	Prepronicomicin-1 of 239 aas		Prepronicomicin-1 of Nicomache minor

1.C.81.1.3	Leukocyte cell-derived chemotaxin 1-like protein of 240 aa		Leukocyte cell-derived chemotaxin 1-like peptide of Lingula anatina

1.C.81.1.4	Uncharacterized protein of 285 aas and 1 TMS.		UP of Exaiptasia pallida

1.C.81.1.5	Leucocyte cell-derived chemotaxin protein 1 of 359 aas		Leucocyte cell-derived chemotaxin protein 1 of Callorhinchus milii

1.C.81.1.6	Uncharacteerized protein of 331 aas		UP of Stylophora pistillata

1.C.81.1.7	*Gastrokine-3-like protein of 181 aas and 1 - 5 TMSs. GKN3 is a host cell receptor for Japanese Encephalitis virus entry into neurons (Mukherjee et al.* 2018).**		Gastrokine-3-like protein of Xenopus laevis

1.C.81.1.8	Leukocyte cell-derived chemotaxin protein 1 isoform 2 precursor of 333 aa		Chemotaxis protein of Homo sapiens

Examples:
TC#	Name	Organismal Type	Example
1.C.81.2.1	Integral membrane protein 2B, ITM2B or BRI2, of 266 aas and 1 TMS. Binds to and regulates the activity of GLUT9, a sugar/urate transporter (TC# 2.A.1.1.72). ITM2B inhibits urate uptake, but stimulates its efflux (Mandal and Mount 2019). Hyperuricemia plays a critical causative role in gout, but has a protective effect in neurodegenerative disorders, including Alzheimer's disease. Genetic variation in the SLC2A9 gene, encoding GLUT9, exerts the largest single-gene effect on serum uric acid. It plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. It also plays a role in the induction of neurite outgrowth and functions as a protease inhibitor by blocking access of secretases to APP cleavage sites. It also facilitates glutamate transmission via both pre- and post-synaptic mechanisms (Yao et al. 2019). It is thus an anti-Alzhemer's disease protein (Matsuda and Senda 2019). The ITM2B interactome in the human retina has been studied (Wohlschlegel et al. 2021). The role of BRI2 in health and disease has been reviewed (Martins et al. 2021).		ITM2B of Homo sapiens

1.C.81.2.2	Integral membrane protein, Itm2A, of 263 aas and 1 vey hydrophobic TMS near the N-terminus, plus 3 moderately hydrophobic putative TMSs near the C-terminus of the protein. Constitutive overexpression of Itm2A enhances myogenic differentiation (Van den Plas and Merregaert 2004). Antibodies against ITM2A are internalized in ITM2A-overexpressing HEK293 cells, and ITM2A is expressed in brain microvessels (Cegarra et al. 2022).		Itm2A of Homo sapiens

1.C.81.2.3	Integral membrane protein 2C, Itm2C (BRI3, Hucep-14, NPD018), of 267 aas with 1 strongly hydrophobic TMS near the N-terminus. It is a negative regulator of amyloid-beta peptide production, and may inhibit the processing of APP by blocking its access to alpha- and beta-secretase (Gong et al. 2008). Binding to the beta-secretase-cleaved APP C-terminal fragment is negligible, suggesting that ITM2C is a poor gamma-secretase cleavage inhibitor. It may also play a role in TNF-induced cell death and neuronal differentiation (Matsuda et al. 2009).		Itm2C of Homo sapiens